Annals of Medicine and Surgery 72 (2021) 103077

Contents lists available at ScienceDirect

Annals of Medicine and Surgery

journal homepage: www.elsevier.com/locate/amsu

Review

An up to date on clinical prospects and management of osteoarthritis

Mudasir Maqbool a, Ginenus Fekadu b, c, *, Xinchan Jiang b, Firomsa Bekele d, Tadesse Tolossa e,
Ebisa Turi e, Getahun Fetensa f, Korinan Fanta g
a
Department of Pharmaceutical Sciences, University of Kashmir, Hazratbal Srinagar, 190006, Jammu and Kashmir, India
b
School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T, Hong Kong
c
School of Pharmacy, Institute of Health Sciences, Wollega University, Nekemte, Ethiopia
d
Department of Pharmacy, College of Health Science, Mettu University, Mettu, Ethiopia
e
Department of Public Health, Institute of Health Sciences, Wollega University, Nekemte, Ethiopia
f
School of Nursing and Midwifery, Institute of Health Sciences, Wollega University, Nekemte, Ethiopia
g
School of Pharmacy, Institute of Health Science, Jimma University, Jimma, Ethiopia

A R T I C L E I N F O A B S T R A C T

Keywords: The rising prevalence of osteoarthritis (OA) in the general population has necessitated the development of novel
Clinical prospects treatment options. It is critical to recognize the joint as a separate entity participating in degenerative processes,
Inflammatory cytokines as well as the multifaceted nature of OA. OA is incurable because there is currently no medication that can stop
Pain pathology
or reverse cartilage or bone loss. As this point of view has attracted attention, more research is being directed
Pharmacotherapy
toward determining how the various joint components are impacted and how they contribute to OA patho­
Osteoarthritis
genesis. Over the next few years, several prospective therapies focusing on inflammation, cartilage metabolism,
subchondral bone remodelling, cellular senescence, and the peripheral nociceptive pathway are predicted to
transform the OA therapy landscape. Stem cell therapies and the use of various biomaterials to target articular
cartilage (AC) and osteochondral tissues are now being investigated in considerable detail. Currently, laboratory-
made cartilage tissues are on the verge of being used in clinical settings. This review focuses on the update of
clinical prospects and management of osteoarthritis, as well as future possibilities for the treatment of OA.

1. Introduction predicted to be the fourth major disability issue in India’s elderly pop­
ulation, with a prevalence of up to 56.6% [6]. In the United States,
Osteoarthritis (OA) is a general term that incorporates several osteoarthritis affects more than 32 million people, although statistics
different joint diseases. OA’s main effects include cartilage degradation, vary according to how the disease is interpreted. Osteoarthritis is the
acute and chronic synovial inflammation, subchondral bone alteration, most prevalent articular disease worldwide. Estimates of its prevalence
the presence of osteophytes, and changes in synovial fluid (SF) [1]. The vary significantly among populations [7,8]. The present review aimed to
first studies on OA were conducted about 130 years ago, and we now provide an update on the pathology and drug regimens of OA and the
recognize OA as a multifactorial, complex disorder. OA was once latest advancements in pharmacotherapy for OA.
believed to be a degenerative condition, but it is now known to have an
infectious cause, as well as a metabolic etiology, according to recent 2. OA’s inflammatory pathology
research [2,3].
A declining younger workforce would sustain an aging population, Cytokines are a group of secreted polypeptides that are essential for
resulting in a demographic problem around the world. According to the initiation of inflammation. Additionally, these cytokines are divided
predictions, Asia’s elderly population will double by approximately into those released in response to acute or chronic inflammation [9–11].
6.8% in 2008 to 16.2% in 2040 [4]. By the age of 65, most people have Several cytokines are important for the mediation of acute inflammatory
radiographic proof of OA, and by the age of 75, about 80% of people reactions, including TNF-α, IL-1, IL-11, IL-8, and IL-6. TNF-α and IL-1 (α
have radiographic proof of OA. Despite its public health implications, and β) are two of the most active inflammatory agents found in the body.
epidemiologists are still affected by OA [5]. For example, OA is Chronic inflammation can occur as a result of acute inflammation,

* Corresponding author. School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
E-mail address: [email protected] (G. Fekadu).

https://doi.org/10.1016/j.amsu.2021.103077
Received 26 September 2021; Received in revised form 14 November 2021; Accepted 16 November 2021
Available online 19 November 2021
2049-0801/© 2021 The Authors. Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
M. Maqbool et al. Annals of Medicine and Surgery 72 (2021) 103077

which can last for weeks, months, or even years, as the name suggests pain and potentially sensitizing nociceptors [35,38].
[12–14]. Nerve dysfunction causes neuropathic pain, which can be detected in
Cytokines implicated in chronic inflammatory processes are divided people with OA using questionnaires that measure the type and intensity
into those that contribute to humoral inflammation, such as IL-3, IL-4, of pain stimuli [40,41]. Neurotransmitters are secreted into the spinal
IL-5, IL-6, IL-7, IL-9, IL-10, IL-13, and TGF-, and those that contribute to cord as a result of prolonged stimulation of pain fibers in OA and other
cellular inflammation, such as IL-1, IL-2, IL-3, IL-4, IL-7, IL-9, IL-10, IL- chronic pain disorders, resulting in increased synaptic regulation and
12, and transforming growth factor-beta [15,16]. Another significant peripheral and central pain perception [35,38]. Cytokines can activate
cytokine implicated in OA pathology and disease onset is TNF-α [17]. neurons directly or indirectly, slowing their firing rate and causing
TNF-α stimulates the secretion of proteolytic enzymes by chondrocytes changes [33,42].
and synovial fibroblasts, which play a key role in apoptotic cell death, Dormant silent nociceptors in a joint may be activated by inflam­
inflammation, and matrix degradation. Therefore, the early inflamma­ matory mediators. Afferent terminals in the joints contain chemical
tory process is initiated by biochemical disturbances and molecular mediators called neuropeptides, which can induce neurogenic inflam­
activity, which also determines the extent of the inflammatory response mation [33,42]. Furthermore, neurogenic inflammation is thought to
[18,19]. cause joint damage by encouraging and exacerbating the inflammatory
There is evidence that IL-3 is released in response to pathophysio­ response [43].
logical conditions; however, it is also likely that it regulates bone
metabolism in both natural and abnormal circumstances [20]. The pro- 4. Management of OA
and anti-inflammatory effects of IL-6, which is formed by several
non-lymphoid and lymphoid cells, as well as chondrocytes and osteo­ 4.1. Non-pharmacological management
blasts in OA, are well established. IL-6 has the capacity to inhibit cata­
bolic factors implicated in cartilage degeneration while also inducing There is convincing evidence that standard exercise programs can
inflammation, indicating that it has a dual role in disease pathology. The significantly reduce pain and enhance physical function in patients with
majority of patients with OA have IL-6 found in their SF, which is knee OA. As a result, acupuncture, aquatic exercise, electroacupuncture,
directly linked to cartilage degradation [21]. inferential current, kinesio taping, manual therapy, moxibustion, pulsed
Local inflammation and synovial tissue loss are also linked to IL-17, a electromagnetic fields, tai chi, ultrasound, yoga, and whole-body vi­
pro-inflammatory cytokine. The presence of IL-17 in the blood, SF, and bration all have silver proof backing them up [44]. Surgical manage­
synovium biopsy samples in patients with OA is strongly linked to the ment is also alternative non pharmacological treatment among eligible
occurrence of knee OA (increasing KL grade). SF IL-17 may be a valuable patients. Some non-pharmacologic rehabilitative interventions are
biochemical predictor of the incidence and progression of knee OA summarized as follows.
[22–24].
IL-4 is an anti-inflammatory cytokine that inhibits the growth and 4.1.1. Exercise
effects of IL-1 and TNF-α. IL-4 stimulates neuronal responses by binding Almost all international recommendations recommend exercise as a
to multimeric receptors. It inhibits chondrocyte development of metal­ first-line treatment for patients with OA. Exercise is recommended as a
loproteinases in response to IL-1 in vitro and has chondroprotective recovery option for patients with knee OA who want to improve their
properties [25,26]. physical function while also reducing pain [45,46]. Exercise, on the
IGF-1 is essential for articular cartilage homeostasis because it acti­ other hand, was discovered to have a pain-relieving effect similar to that
vates chondrocytes to generate matrix proteins, inhibits their degrada­ of simple analgesia or non-steroidal anti-inflammatory drugs, but with
tion, and prevents cell death. Increases in IGF-1 activity are assumed to fewer side effects. Although previous research indicated that exercise
be an effort by cartilage to re-establish homeostasis in OA, but they are had limited pain-relieving and physical-functioning benefits, a new
mostly unsuccessful [27–30]. study discovered that exercise had a significant positive effect on
The exact pathophysiology of OA remains unclear. Oxidative stress symptomatic hip OA patients [46,47].
and chronic inflammation in the synovium, on the other hand, are Aerobic training also improves resistance training’s muscle-
known to intensify cartilage degeneration and synovitis, an acute con­ strengthening properties, which, as previously stated, has beneficial
dition of inflammation. SF proteome/cytokine profiling, on the other effects [48,49]. Patients should be informed about the disease’s
hand, reveals the existence of both pro- and anti-inflammatory causes. everyday variability and how over-exercising can affect them, which can
The proportion of inflammatory factors is thought to increase as the manifest as increased pain during operations lasting more than 1 or 2 h,
disease progresses, resulting in increased cartilage degradation [31,32]. edema, exhaustion, and muscle fatigue [50,51]. However, the patient’s
It is interesting to see how these causes affect cartilage loss as well as education should not instill fear of activity, as this is often linked to a
acute synovial inflammation [32]. poor care response [49].

3. Pathology of pain in OA 4.1.2. Physical therapy (heat and cooling)

Heating decreases discomfort while also increasing the expression of
There is no direct link between the degenerative phase of cartilage in heat shock protein 70 (HSP 70), which has a relaxing and calming effect
OA and pain [33,34]. Nerve fibers provide information to the synovial on OA patients. HSP 70 is involved in cartilage defense, reducing
membrane, ligaments, outer menisci, and subchondral bone. Chronic inflammation, and preventing chondrocyte apoptosis [52,53]. To date,
pain has an emotional dimension, although the main mechanisms of pain relief has been the only benefit of shallow cold therapy [54].
pain signal processing are unclear [35,36]. Mental health problems are
common comorbidities among patients with OA, but they have been 4.1.3. Neuromuscular electrical stimulation (NMES)
linked to severe pain [37]. Neuromuscular electrical stimulation (NMES) is also controversial in
Pain is a complex neurological syndrome that affects patients with women with moderate to severe osteoarthritis of the knee. NMES has
OA and is believed to be regulated by both nociceptive and neuropathic been shown to have no effect on quadriceps muscle strengthening [50].
pathways [38]. As nociceptors are stimulated mechanically or chemi­ The Cochrane Review found no improvement in isometric resistance
cally in response to local tissue damage, a pain signal is transmitted from despite signs of improved quadriceps muscle activation [50,55].
the joint to the dorsal root ganglion of the spinal cord and then up the
spinothalamic tract to cortical processing centers [36,39]. Chemical 4.1.4. Pulsed electromagnetic field therapy (PEMF)
impulses are produced when a tissue is damaged, causing physiological According to a meta-analysis of the PEMF RCT, PEMF

2
M. Maqbool et al. Annals of Medicine and Surgery 72 (2021) 103077

implementation in OA management greatly increased the patient’s daily category. Topical and intra-articular therapies have also been used [70,
operation. There was no increase in pain or stiffness, on the other hand 71]. Palliative pain management is the primary focus of current OA
[56,57]. The OA guidelines list PEMF therapy as an alternative to other management strategies. Joint replacement surgery has been shown to
treatment options. Physiotherapy and other less expensive methods of relieve the disease’s excruciating and disabling symptoms in acute cir­
medication have similar benefits to PEMF. Consequently, PEMF can be cumstances. Currently, no treatments are available to slow or reverse the
replaced by physical therapy, at least in some cases [58]. development of OA [72,73]. Therapeutic solutions for OA are divided
into multiple groups, as shown in Fig. 1. The existing care strategies for
4.1.5. Transcutaneous electrical nerve stimulation OA are directed mainly at reducing pain and discomfort, maintaining
Transcutaneous electrical nerve stimulation (TENS) is a pain- joint stability, and avoiding function loss [73,74].
relieving procedure that can be used to treat a wide range of medical Patient screening, diet, yoga, weight loss, acupuncture, and physical
problems. It is often used for severe pain or in cases where pharmaco­ rehabilitation, which include thermotherapy, transcutaneous electrical
therapy fails [59,60]. TENS has also been shown to be successful in the nerve stimulation (TENS), and short-wave diathermy, are all non-
treatment of OA. TENS associated with exercise reduced pain and pharmacological treatments [75,76].
increased quadriceps muscle activation, resulting in better physical ac­
tivity [50]. 4.2.1. NSAIDs and analgesics
NSAIDs may be used to help with other conditions, including joint
4.1.6. Low-level laser therapy pain. Oral analgesics, including acetaminophen, ibuprofen, diclofenac,
Low-level laser therapy (LLL) combined with exercise has been and cyclooxygenase type 2 (COX-2) antagonists, as well as intra-
shown to alleviate pain while improving mobility and movement in articular corticosteroids, are often used to alleviate arthritis discom­
patients with knee OA. Radiation also increases local microcirculation fort [77,78].
and is highly recommended as a supplement to other treatments for OA
[50,61]. 4.2.2. Topical agents
Among them are topical lidocaine, NSAIDs, and capsaicin. By
4.1.7. Massage maximizing local absorption, thus minimizing systemic toxicity, topical
Massage for 60 min a week after eight weeks of therapy increased application of NSAIDs decreases the harmful effects of oral medications
pain management and the Western Ontario and McMaster Universities [79,80].
Arthritis Index (WOMAC) functionality scores [62,63]. There was no
discernible difference between the experimental and normal treatments 4.2.3. Intra-articular therapy
after 24 weeks. The repositioning of the affected knee joint was not OA is also treated with corticosteroid injections into articular carti­
facilitated by relaxing massage of the quadriceps, gracilis, femoris, lage. Methyl prednisolone acetate, betamethasone acetate/betametha­
sartorious, and hamstrings [50,64]. sone sodium phosphate, triamcinolone acetonide, triamcinolone
hexacetonide, and betamethasone dipropionate/betamethasone sodium
4.1.8. Acupuncture phosphate are among the most frequently prescribed preparations [81,
Despite its efficacy, the use of acupuncture in the treatment of OA 82].
requires further research. Any of the effects may be due to the patient’s
anticipation, the placebo effect, or even pain relief, both of which 4.2.4. Hyaluronic acid
contribute to improved posture. It also depends in part on the Hyaluronic acid is a structural polysaccharide present in the cartilage
acupuncturist, who may or may not have prior experience. As a result, extracellular matrix that plays a crucial role in the development of SF
more research should be conducted to determine its true efficacy using a [83]. It is important to maintain the viscoelastic properties of SF because
double-blind design, so that its use can be checked [50,65]. it functions as a lubricant and shock absorber [84].

4.1.9. Assistive devices 4.2.5. Anti-cytokine therapy

Chondrocytes and synoviocytes, such as immune cells, can produce a
4.1.9.1. Canes. Patients with OA frequently use canes to aid in variety of pro-inflammatory cytokines. Many cytokines are involved, but
mobility. When patients first use it, their energy expenditure tends to tumor necrosis factor-alpha (TNF-α) is required for the initiation and
increase. However, after one month, the benefits of using canes could be regulation of inflammatory cascades. TNF-α promotes the development
seen in the form of significant pain reductions and a return to normal of cytokines and tissue-degrading enzymes such as matrix metal­
energy expenditure because of the adaptation. The cane should be used loproteinases (MMPs) [85]. TNF-α is a cytokine produced by monocytes,
contra-laterally to significantly reduce the burden on the affected knee macrophages, T and B cells, as well as synoviocytes, and its levels in­
while maximizing the benefit [50,66]. crease as the condition worsens. TNF-α antibodies have been shown to
significantly minimize joint inflammation and pain [86,87].
4.1.9.2. Braces and insoles. Lateral wedges reduce the knee-ground Infliximab, golimumab, etanercept, certolizumab pegol, and adali­
response force lever arm in patients with medial knee OA, which mumab are five anti-TNF agents that have been documented for the
tends to be the primary cause of load-reduction effects. The impact of treatment of rheumatoid arthritis. The complementarity-determining
valgus knee braces and lateral wedged insoles on biochemistry and region of a murine anti-human IL-6R (IL-6 receptor) antibody was
health outcomes were contrasted in a recent study [67,68]. Both ther­ combined with human IgG1 to create this humanized monoclonal
apies can help delay the progression of the disease by reducing knee antibody. Tocilizumab is an anti-inflammatory medication that prevents
loading in patients with OA. Action levels are raised when valgus un­ the activation of the IL-6 receptor [88,89]. Anakinra blocks the bio­
loader braces are worn [66,69]. logical function of naturally occurring IL-1by competitively inhibiting
IL-1 binding to IL-1R, which is expressed in a variety of tissues and or­
gans [90].
4.2. Pharmacological management
4.2.6. Omega-3 fatty acids as dietary supplements
The primary goal of pharmacological OA therapy is to alleviate the Eicosanoids are mediators as well as regulators of inflammation, and
symptoms of OA. Nonsteroidal anti-inflammatory drugs (NSAIDs) and PUFAs are essential fatty acids that produce them. Omega-3 PUFA
analgesics are the most frequently prescribed medications in this therapy reduced pro-inflammatory factors and improved anti-

3
M. Maqbool et al. Annals of Medicine and Surgery 72 (2021) 103077

Fig. 1. Holistic therapies for the management of osteoarthritis.

inflammatory markers in preclinical and clinical trials [91,92]. In human beings is assumed to be completely safe [102,103]. However,
cartilage cell cultures, omega-3 PUFAs have also been shown to inhibit one laboratory trial of these analgesic combinations was shown to have
the transcription of essential matrix degradation enzymes and cytokines the ability to alleviate OA pain, while others were shown to slow
[93]. cartilage deterioration, in which excessive Vata energy causes pain,
Curtis et al. examined how omega-3 and omega-6 fatty acids affect immobility, and rigidity of the limbs [104,105].
the history of human OA cartilage explants. These findings indicate that Over the last several years, there has been an increased focus on the
omega-3 supplementation can fully suppress the expression of ADAMTS- molecular mechanisms of how herbal drugs work in the body. The
4, MMP-13, and MMP-3 in the body, as well as other pro-inflammatory ancient Ayurvedic formulations Triphala churna and Triphaghula, along
mediators (5-lipoxygenase, cyclooxygenase 2, 5-lip­ with Balaraja and Dashmoolasa, are used to treat the disease [105,106].
oxygenase–activating enzyme, tumor necrosis factor, and interleukin-1) According to ancient texts, triphala and its components have
[94]. anti-inflammatory, antioxidant, cytoprotective, and rejuvenating effects
Another study established that supplementation with EPA and DHA (Rasayana) [107,108].
blocked the deterioration of cartilage caused by IL-1β [95]. The In pharmacological research, triphala extract has been shown to have
involvement of EPA and DHA was found to inhibit the release of sGAGs free radical scavenging properties and to minimize the damage caused
from cartilage explants induced by IL-1β. Additionally, fish oil supple­ by oxidative stress. Triphala has also been shown to scavenge nitric
mentation in combination with NSAIDs has been shown to alleviate oxide (NO) in vitro, as well as exert anti-inflammatory and anti-arthritic
discomfort and enhance the weight-bearing capability of knee cartilage effects [109,110]. Triphala reduces inflammatory mediator levels and
in laboratory dogs [96]. inhibits lipid peroxidation. Dashamoola formulations are made up of the
Fritsch et al. (2010) discovered that feeding a fish oil-rich diet to roots of ten plants that are also useful for vata-roga, as the name sug­
dogs with OA for 12 weeks reduced caporofen (NSAID) dosage signifi­ gests. Dashamoolarishta has been used for its anti-inflammatory effects
cantly compared to a control diet. Omega-3 fatty acid supplementation as well as for the relief of inflammation and discomfort associated with
was used to treat OA-prone and OA-resistant guinea pig strains using a arthritis since ancient times [111,112].
random OA model in a significant trial [97]. When OA-prone and-re­ In conclusion, Ayurveda mentioned a variety of polyherbal formu­
sistant strains were compared, OA markers such as lysyl-pyridinoline, lations with a long history of medical use in OA, and many of these
active MMP-2, and complete collagen cross-links were altered. When formulations are successful in reducing tissue inflammation in OA
compared to a non-pathological strain fed an omega-3 diet, subchondral models. As a result, Ayurvedic therapies are emerging as a ray of hope
bone parameters such as calcium to phosphate ratios and epiphyseal for treating a variety of chronic diseases without the use of potentially
bone density improved significantly [97,98]. risky medications. The current OA drug treatments with the available
Omega 3 fatty acids have been shown to have anti-inflammatory phenotypes are described in Table 1.
properties in a variety of animal models and clinical trials [99]. Tak­
ing an omega-3 fatty acid supplement has been shown in some trials to
significantly improve OA symptoms in the knee cartilage and the lower 4.3. Surgical management
portion of the femur (one of the vertebrae) [100,101].
Many people with osteoarthritis develop to severe joint degeneration
4.2.7. Herbs and Ayurvedic formulations in the absence of disease-modifying medication. As a result, surgery is
Although several herbs have been used in Ayurveda for many years, crucial in the treatment of OA. Biomaterials and tissue engineering ad­
many of them are commonly used in human remedies; their use in vancements will continue to open up interesting new possibilities for
integrating surgical techniques into OA treatment. Weak study designs

4
M. Maqbool et al. Annals of Medicine and Surgery 72 (2021) 103077

Table 1
Current drug treatments for OA with available phenotypes.
Target Drug categories Findings References

A) Treatments for cartilage problems

Inhibition of cartilage matrix MMP-inhibitor PG-116800 Termination due to musculoskeletal toxicity [113,
degradation 114]
Cartilage matrix regeneration Sprifermin (truncated human FGF18) The thickness of the cartilage of the femorotibial joint has [113,115]
improved.
BMP-7 or OP-1 Both the BMP-7 and placebo participants experienced pain [113,116]
relief.
B) Subchondral bone treatment options
Bisphosphonates/bone Zoledronic acid BML size has shrunk, as has the pain score on the visual [113,117]
turnover analogue scale.
Risedronate BMLs reduced discomfort in a patient subgroup. [113,118]
AXS-02 (disodium zoledronate tetrahydrate) BMLs reduced discomfort in a patient subgroup. [113,119]
Inhibition of bone degradation Cathepsin K inhibitor MIV-711 Slowdown of bone and cartilage degeneration [113,120]
C) Inflammatory-process-targeting therapies
IL-1 Anakinra (IL-1 receptor antagonist) No improvements of OA symptoms [113,121]
AMG 108 (fully human monoclonal antibody to IL-1R1) Minimal clinical benefit [113,122]
Lutikizumab (anti IL-1 α/β antibody) No improvement in synovitis, minimal effect on WOMAC pain [113,123]
score
Tumor necrosis factor-alpha Adalimumab There was no difference in discomfort, synovitis, or BMLs [113,124]
Increased physical activity and effective pain relief [113,125]
Etanercept There is little pain relief, and MMP-3 concentration in the [113,126]
body was decreasing.
Infliximab Treatment of recent-onset RA patients slowed the [113,127]
development of hand OA.
Toll-like receptor 7/9 Hydroxychloroquine Efficacy was not shown. [113,128]
I-kB kinase SAR113945 (I-kB kinase inhibitor) No superior efficacy [113,129]
p38 MAP kinase FX-005 Pain relief superior to placebo [113]
D) Treatments that target the causes of pain
NGF Tanezumab (anti-NGF antibody) Although there has been a small improvement in functional [113,130]
and pain ratings, the rising demand for joint replacement has
raised safety concerns.
NGF receptor tropomyosin- Pan Trk inhibitor GZ389988 Short-term moderate pain reduction compared to control [113,131]
related kinase A (TrkA)
Transient receptor potential Trans-capsaicin (CNTX-4975) Over the course of 24 weeks, intra-articular CNTX-4975 [113,132]
vanilloid 1 (TRPV1) minimised moderate-to-severe pain relative to placebo.
receptor
Mavatrep (JNJ-39439335) Significant pain relief and improved function were achieved, [113,133]
but dosage changes were needed due to altered heat
sensitivity and the subsequent thermal burns.
Kappa-opioid receptor Selective agonist CR845 Dose-dependent pain relief is more successful in patients with [113,133]
hip OA.
Alpha calcitonin gene-related Galcanezumab (LY2951742) The study was halted due to insufficient efficacy. [113,134]
peptide
Imidazoline receptor I2 CR4056 (receptor ligand) Analgesia that works, particularly in men and patients with [113,135]
metabolic syndrome who are overweight.
E) Medications for the metabolic syndrome
Cox-2 and T2DM Cox-2 inhibitor and metformin Lower rate of receiving joint replacement surgery [113,136]
HMG-CoA-Reductase Statins: simvastatin, atorvastatin, atorvastatin calcium, lovastatin, Regardless of other possible confounding variables, [113,137]
fluvastatin sodium, nystatin, pravastatin, pravastatin sodium, radiological deterioration over 3 years
rosuvastatin, and rosuvastatin calcium
Statins: atorvastatin, fluvastatin, pravastatin, rosuvastatin, or No protective effect of statins on the risk of developing hand [113,137]
simvastatin OA
Statins: pravastatin, simvastatin, fluvastatin, rosuvastatin, The use of statins is not linked to a lower risk of hip or knee OA [113,138]
lovastatin, and atorvastatin consultations or surgeries.

and small samples limit the data supporting the utility of various sur­ therapy combined with physical therapy in randomized trials [143].
gical procedures. Scientific breakthroughs in the field will require For severe clinical illness that has not responded to conservative
extensive examinations of the efficacy and cost effectiveness of surgical treatment, joint replacement surgery should be considered. In persons
approaches to OA therapy [139,140]. who are getting physical and medicinal therapy for knee osteoarthritis,
Surgery could be used if alternative treatments have failed to alle­ arthroscopic operations have not offered any further benefit [143–145].
viate the patient’s symptoms. Consistent pain and disability despite Surgery should be considered if conservative therapy fails. Arthroscopy,
conservative treatment are a well-accepted indication for surgery. Total cartilage repair, osteotomy, and knee arthroplasty are surgical treat­
joint replacement is the most effective surgical procedure, with good ments for knee OA. The location, stage of OA, comorbidities, and pa­
patient outcomes after hip, knee, and shoulder replacements. There are a tients suffering on the other side all play a role in determining which of
variety of prosthetic devices available, but there are no controlled trials these operations is most suited. Arthroscopic lavage and debridement
comparing them. Most contemporary joint prosthesis are expected to are frequently performed; however they have no effect on disease
last 15–20 years for most patients [141,142]. Other surgical treatments development. Unicompartmental (partial) knee arthroplasty or
for osteoarthritis exist, but none have shown to be as effective as total unloading osteotomy may be explored if OA is restricted to one
joint replacement. Arthroscopic debridement for osteoarthritis of the compartment. Because of the dangers and limited durability of complete
knee has continuously failed to show a benefit over maximal medical knee replacement, they are indicated in young and active patients. In

5
M. Maqbool et al. Annals of Medicine and Surgery 72 (2021) 103077

older patients with advanced knee OA, total knee arthroplasty is a unresolved. Gene therapy could be another advanced treatment option
routine and safe procedure [146,147]. for OA.
Furthermore, reversing the derailment of cellular mechanoreceptive
5. Available gaps and future therapies pathways may open new avenues for preventing structural tissue
degradation. Although many issues remain, these approaches show
In the pathogenesis of osteoarthritis, the matrix-degrading enzymes enormous potential for the future; nonetheless, success will only be
MMP-13 and ADAMTS-5 play a role. In a mouse model of osteoarthritis, achieved if efforts are united. To establish a valid strategy for OA in
CL82198, an inhibitor of MMP-13, inhibited chondrocyte apoptosis and healthcare, researchers and doctors must collaborate.
delayed cartilage degradation [148]. However, such findings in humans
are yet to be verified. Due to musculoskeletal toxicity, the only MMP 6. Conclusion
blocker clinical trial (PG-116800) has been halted [149]. MMP-1 and
MMP-7 are two MMPs that are thought to play a role in the progression Osteoarthritis (OA) severely restricts the everyday activities of senior
of musculoskeletal toxicity, and PG-116800 binds to both MMPs [150]. citizens. The frequency and prevalence of OA are anticipated to double
Further research is needed to fully evaluate the efficacy and safety of over the next decade. Patients with osteoarthritis seek medical help
MMP inhibitors. Chen et al. examined the use of an ADAMTS-5 blocker because of their suffering. While IL-6 can suppress catabolic pathologies
to treat osteoarthritis in mouse knee joints [151]. After eight weeks, a associated with cartilage degeneration, it can also drive cartilage
combination of an ADAMTS-5 inhibitor (114810) and hyaluronic acid degeneration. OA has seen quite a bit of change over the past few years.
hydrogel reduced cartilage degeneration and allowed cartilage regen­ Nonnarcotic analgesics, such as nutraceuticals and intraarticular drugs,
eration, implying that ADAMTS-5 may be a target for osteoarthritis are some of the new and more efficacious agents, such as those in the
treatment. market.
ADAMTS-5 activation has also been linked to Syndecan-4 [152]. As a The more advanced the understanding and use of non­
result, using a syndecan-4-specific antibody inhibits the activation of pharmacological interventions (such as patients, exercise, and weight
ADAMTS-5, thereby slowing the progression of osteoarthritis. Although reduction when needed), and the more frequently they are applied, the
articular cartilage has been the focus of most clinical target trials, sub­ better the results. In most patients, pain relief and the ability to move or
chondral bone can also be implicated in the disease phase. TGF-β has use their joints can be obtained using an integrated approach. When it
been established as a key player in subchondral bone formation. comes to the many routes that are used, a single-targeted approach is not
Zhen et al. discovered TGF-β activation in the subchondral bone in likely to address the problem. Thus, as with other long-term diseases, OA
response to changed mechanical loading in a mouse osteoarthritis model treatment has the potential to improve.
with anterior cruciate ligament transection [153]. Inhibition of TGF-β
activity in the subchondral bone also decreased articular cartilage Ethical approval
degeneration. Furthermore, the Wnt/β-catenin signalling pathway may
be a viable option [154]. Dkk-1 suppression was found to improve Not applicable.
osteoarthritis in a mouse model in a recent report [155]. These results
emphasize the importance of treating osteoarthritis as a whole-joint Source of funding
condition.
Recent developments in OA pathology have shown the critical This research did not receive any specific grant from funding
functions of several novel pathways that can be addressed. However, agencies in the public, commercial, or not-for-profit sectors.
because OA is a diverse illness, a single medication targeting a specific
joint tissue may be ineffective, and no “one-size-fits-all” drug or therapy
Authors’ contribution
will ever be discovered. Timely changes in disease development, such as
the switch from high bone turnover in early OA to lower bone turnover
MM, GF* and XJ drafted the review and contributed to the writing of
later, or changes in pain type, necessitate accurate knowledge of the
the manuscript. FB, ET, TT, GF and KF provided critical input and
underlying molecular alterations.
revised the manuscript. All authors critically revised the manuscript,
In the future, selecting appropriate medication for specific disease
accountable for all aspects of the work and approved the final version to
time-points could aid in tailoring personalized treatment regimens for
be published.
each patient. Furthermore, OA may present with overlapping endotypes,
such as an inflammatory pain endotype that could benefit from a com­
Consent for publication
bination of pain and inflammation-fighting medications [113]. Over the
next few years, several prospective therapies focusing on inflammation,
Not applicable. No individual personal details, images, or videos
cartilage metabolism, cellular senescence, subchondral bone remodel­
were being used in this study.
ling, and the peripheral nociceptive pathway are predicted to transform
the OA therapy landscape.
The most promising treatments are those that target articular carti­ Registration of research studies
lage molecular processes [156–158]. The development of new thera­
peutic options for OA will require better knowledge of the disease. 1. Name of the registry: Not applicable
However, according to the literature, traditional repair strategies 2. Unique Identifying number or registration ID: Not applicable
continue to predominate in clinics. The first treatment for OA patients is 3. Hyperlink to your specific registration (must be publicly accessible
mainly conservative management and pharmaceutics. These methods and will be checked): Not applicable
can help relieve pain and improve joint functionality and may even help
to slow the progression of OA. Provenance and peer review
There are various options for chondrocytes and stem cells, such as
mesenchymal stem cells and adipose-derived stem cells, as cell sources. Not commissioned, externally peer reviewed.
Concerns regarding efficient supply, safety, the creation of non-
specialized tissue, cancer, and legal difficulties must be addressed Guarantor
[159,160]. Moreover, the standardization of the method, which includes
biomaterial synthesis, cell separation, and maintenance, remains Ginenus Fekadu.

6
M. Maqbool et al. Annals of Medicine and Surgery 72 (2021) 103077

Availability of data and materials [19] Y. Zhao, Y. Li, R. Qu, X. Chen, W. Wang, C. Qiu, B. Liu, X. Pan, L. Liu, K. Vasilev,
Cortistatin binds to TNF-α receptors and protects against osteoarthritis,
EBioMedicine 41 (2019) 556–570.
The datasets used and/or analyzed during the current study were [20] J. Oh, M.S. Lee, J.T. Yeon, S.W. Choi, H.S. Kim, H. Shim, S.Y. Lee, B.S. Youn,
included in the published article. Y. Yokota, J.H. Kim, Inhibitory regulation of osteoclast differentiation by
interleukin-3 via regulation of c-Fos and Id protein expression, J. Cell. Physiol.
227 (2012) 1851–1860.
Declaration of competing interest [21] O. Stannus, G. Jones, F. Cicuttini, V. Parameswaran, S. Quinn, J. Burgess, C. Ding,
Circulating levels of IL-6 and TNF-α are associated with knee radiographic
osteoarthritis and knee cartilage loss in older adults, Osteoarthritis Cartilage 18
The authors declare that they have no competing interests. (2010) 1441–1447.
[22] H.-Y. Yang, Y.-Z. Liu, X.-D. Zhou, Y. Huang, N.-W. Xu, Role of IL-17 gene
polymorphisms in osteoarthritis: a meta-analysis based on observational studies,
Acknowledgments
World journal of clinical cases 8 (2020) 2280.
[23] H.S. Na, J.-S. Park, K.-H. Cho, J.Y. Kwon, J. Choi, J. Jhun, S.J. Kim, S.-H. Park,
Not applicable. M.-L. Cho, Interleukin-1-interleukin-17 signaling axis induces cartilage
destruction and promotes experimental osteoarthritis, Front. Immunol. 11 (2020)
730.
Abbreviations [24] J.Y. Mimpen, M.J. Baldwin, A.P. Cribbs, M. Philpott, A.J. Carr, S.G. Dakin, S.
J. Snelling, Interleukin-17A causes osteoarthritis-like transcriptional changes in
AC Articular Cartilage human osteoarthritis-derived chondrocytes and synovial fibroblasts in vitro,
Front. Immunol. 12 (2021).
IL Interleukin [25] P. Castrogiovanni, M. Di Rosa, S. Ravalli, A. Castorina, C. Guglielmino, R. Imbesi,
LLL Low-level laser therapy M. Vecchio, F. Drago, M.A. Szychlinska, G. Musumeci, Moderate physical activity
MMPs Matrix metalloproteinase as a prevention method for knee osteoarthritis and the role of synoviocytes as
biological key, Int. J. Mol. Sci. 20 (2019) 511.
NMES Neuromuscular electrical stimulation [26] N. Ahmad, M.Y. Ansari, T.M. Haqqi, Role of iNOS in osteoarthritis: pathological
NSAIDs Nonsteroidal anti-inflammatory drugs and therapeutic aspects, J. Cell. Physiol. 235 (2020) 6366–6376.
OA Osteoarthritis [27] M.A. Hossain, A. Adithan, M.J. Alam, S.R. Kopalli, B. Kim, C.-W. Kang, K.-
C. Hwang, J.-H. Kim, IGF-1 facilitates cartilage reconstruction by regulating
SF Synovial fluid PI3K/AKT, MAPK, and NF-kB signaling in rabbit osteoarthritis, J. Inflamm. Res.
TENS Transcutaneous electrical nerve stimulation 14 (2021) 3555.
TNF-α Tumour necrosis factor-alpha [28] I. Pelsma, K.M. Claessen, P.E. Slagboom, D. van Heemst, A. Pereira, H. Kroon, Y.
F. Ramos, M. Kloppenburg, N. Biermasz, I.M. Meulenbelt, Variants of FOXO3 and
WOMAC Western Ontario and McMaster Universities Arthritis Index RPA3 genes affecting IGF-1 levels alter the risk of development of primary
osteoarthritis, Eur. J. Endocrinol. 1 (2020).
References [29] G. Gasparini, M. De Gori, F. Paonessa, E. Chiefari, A. Brunetti, O. Galasso,
Functional relationship between high mobility group A1 (HMGA1) protein and
insulin-like growth factor-binding protein 3 (IGFBP-3) in human chondrocytes,
[1] N. Arden, M.C. Nevitt, Osteoarthritis: epidemiology, Best Pract. Res. Clin.
Arthritis Res. Ther. 14 (2012) 1–9.
Rheumatol. 20 (2006) 3–25.
[30] W.-C. Lo, N.K. Dubey, F.-C. Tsai, J.-H. Lu, B.-Y. Peng, P.-C. Chiang, A.K. Singh, C.-
[2] E.R. Vina, C.K. Kwoh, Epidemiology of osteoarthritis: literature update, Curr.
Y. Wu, H.-C. Cheng, W.-P. Deng, Amelioration of nicotine-induced osteoarthritis
Opin. Rheumatol. 30 (2018) 160.
by platelet-derived biomaterials through modulating IGF-1/AKT/IRS-1 signaling
[3] T. Ibounig, T. Simons, A. Launonen, M. Paavola, Glenohumeral osteoarthritis: an
Axis, Cell Transplant. 29 (2020), 0963689720947348.
overview of etiology and diagnostics, Scand. J. Surg. (2020),
[31] T.M. Griffin, C.R. Scanzello, Innate inflammation and synovial macrophages in
1457496920935018.
osteoarthritis pathophysiology, Clin. Exp. Rheumatol. 37 (2019) 57.
[4] M. Fransen, L. Bridgett, L. March, D. Hoy, E. Penserga, P. Brooks, The
[32] M. Geyer, C. Schönfeld, Novel insights into the pathogenesis of osteoarthritis,
epidemiology of osteoarthritis in Asia, International journal of rheumatic diseases
Curr. Rheumatol. Rev. 14 (2018) 98–107.
14 (2011) 113–121.
[33] K.L. Witt, J.A. Vilensky, The anatomy of osteoarthritic joint pain, Clin. Anat. 27
[5] D. Prieto-Alhambra, A. Judge, M.K. Javaid, C. Cooper, A. Diez-Perez, N.K. Arden,
(2014) 451–454.
Incidence and risk factors for clinically diagnosed knee, hip and hand
[34] A. Heijink, A.H. Gomoll, H. Madry, M. Drobnič, G. Filardo, J. Espregueira-
osteoarthritis: influences of age, gender and osteoarthritis affecting other joints,
Mendes, C.N. Van Dijk, Biomechanical considerations in the pathogenesis of
Ann. Rheum. Dis. 73 (2014) 1659–1664.
osteoarthritis of the knee, knee surgery, sports traumatology, Arthroscopy 20
[6] M. Sharma, H. Swami, V. Bhatia, A. Verma, S. Bhatia, G. Kaur, An
(2012) 423–435.
epidemiological study of correlates of osteo-arthritis in geriatric population of UT
[35] J.J. McDougall, Arthritis and pain. Neurogenic origin of joint pain, Arthritis Res.
Chandigarh, Indian J. Community Med. 32 (2007) 77.
Ther. 8 (2006) 1–10.
[7] D. Pereira, B. Peleteiro, J. Araujo, J. Branco, R. Santos, E. Ramos, The effect of
[36] A.S. Lee, M.B. Ellman, D. Yan, J.S. Kroin, B.J. Cole, A.J. van Wijnen, H.-J. Im,
osteoarthritis definition on prevalence and incidence estimates: a systematic
A current review of molecular mechanisms regarding osteoarthritis and pain,
review, Osteoarthritis Cartilage 19 (2011) 1270–1285.
Gene 527 (2013) 440–447.
[8] D. Pereira, M. Severo, E. Ramos, J. Branco, R.A. Santos, L. Costa, R. Lucas,
[37] G.A. Hawker, S. Mian, T. Kendzerska, M. French, Measures of adult pain: visual
H. Barros, Potential role of age, sex, body mass index and pain to identify patients
analog scale for pain (vas pain), numeric rating scale for pain (nrs pain), mcgill
with knee osteoarthritis, International journal of rheumatic diseases 20 (2017)
pain questionnaire (mpq), short-form mcgill pain questionnaire (sf-mpq), chronic
190–198.
pain grade scale (cpgs), short form-36 bodily pain scale (sf-36 bps), and measure
[9] J. Alam, I. Jantan, S.N.A. Bukhari, Rheumatoid arthritis: recent advances on its
of intermittent and constant osteoarthritis pain (icoap), Arthritis Care Res. 63
etiology, role of cytokines and pharmacotherapy, Biomed. Pharmacother. 92
(2011) S240–S252.
(2017) 615–633.
[38] P.J. Mease, S. Hanna, E.P. Frakes, R.D. Altman, Pain mechanisms in
[10] Y.Y. Chow, K.-Y. Chin, The Role of Inflammation in the Pathogenesis of
osteoarthritis: understanding the role of central pain and current approaches to its
Osteoarthritis, Mediators of inflammation, 2020, p. 2020.
treatment, J. Rheumatol. 38 (2011) 1546–1551.
[11] T. Wang, C. He, Pro-inflammatory cytokines: the link between obesity and
[39] A.K. Aarsand, P.H. Petersen, S. Sandberg, Estimation and application of biological
osteoarthritis, Cytokine Growth Factor Rev. 44 (2018) 38–50.
variation of urinary δ-aminolevulinic acid and porphobilinogen in healthy
[12] M.Y. Ansari, N. Ahmad, T.M. Haqqi, Oxidative stress and inflammation in
individuals and in patients with acute intermittent porphyria, Clin. Chem. 52
osteoarthritis pathogenesis: role of polyphenols, Biomed. Pharmacother. 129
(2006) 650–656.
(2020) 110452.
[40] J.R. Hochman, M.R. French, S.L. Bermingham, G.A. Hawker, The nerve of
[13] K.V. Raymuev, Pro-inflammatory and Anti-inflammatory Cytokines in the
osteoarthritis pain, Arthritis Care Res. 62 (2010) 1019–1023.
Pathogenesis of Osteoarthritis, vol. 10, Herald of North-Western State Medical
[41] S. Ohtori, S. Orita, M. Yamashita, T. Ishikawa, T. Ito, T. Shigemura, H. Nishiyama,
University named after II Mechnikov, 2018, pp. 19–27.
S. Konno, H. Ohta, M. Takaso, Existence of a neuropathic pain component in
[14] J.E. Woodell-May, S.D. Sommerfeld, Role of inflammation and the immune
patients with osteoarthritis of the knee, Yonsei Med. J. 53 (2012) 801.
system in the progression of osteoarthritis, J. Orthop. Res. 38 (2020) 253–257.
[42] Y. Konttinen, T. Sillat, G. Barreto, M. Ainola, D. Nordström, Osteoarthritis as an
[15] M. Daheshia, J.Q. Yao, The interleukin 1β pathway in the pathogenesis of
autoinflammatory disease caused by chondrocyte-mediated inflammatory
osteoarthritis, J. Rheumatol. 35 (2008) 2306–2312.
responses, Arthritis Rheum. 64 (2012) 613.
[16] Z. Jotanovic, R. Mihelic, B. Sestan, Z. Dembic, Role of interleukin-1 inhibitors in
[43] B.L. Kidd, J.J. Inglis, K. Vetsika, V.C. Hood, C. De Felipe, H. Bester, S.P. Hunt, S.
osteoarthritis, Drugs Aging 29 (2012) 343–358.
C. Cruwys, Inhibition of inflammation and hyperalgesia in NK-1 receptor knock-
[17] P. Sharma, N. Singh, V. Singh, S. Singh, H. vardhan Singh, S. Gupta, Tumor
out mice, Neuroreport 14 (2003) 2189–2192.
necrosis factor alpha (TNF-α) and estrogen hormone in osteoarthritic female
[44] R.M. Ferreira, J.A. Duarte, R.S. Gonçalves, Non-pharmacological and non-surgical
patients, Indian J. Clin. Biochem. 21 (2006) 205–207.
interventions to manage patients with knee osteoarthritis: an umbrella review,
[18] C. Xie, Q. Chen, Adipokines: new therapeutic target for osteoarthritis? Curr.
Acta Reumatol Port 43 (2018) 182–200.
Rheumatol. Rep. 21 (2019) 1–9.

7
M. Maqbool et al. Annals of Medicine and Surgery 72 (2021) 103077

[45] L. Pazit, D. Jeremy, B. Nancy, B. Michael, E. George, K.D. Hill, Safety and [70] M. Cutolo, F. Berenbaum, M. Hochberg, L. Punzi, J.-Y. Reginster, Commentary on
feasibility of high speed resistance training with and without balance exercises for Recent Therapeutic Guidelines for Osteoarthritis, Seminars in Arthritis and
knee osteoarthritis: a pilot randomised controlled trial, Phys. Ther. Sport 34 Rheumatism, Elsevier, 2015, pp. 611–617.
(2018) 154–163. [71] M.H. Majeed, S.A.A. Sherazi, D. Bacon, Z.H. Bajwa, Pharmacological treatment of
[46] K. Hanada, M. Hara, Y. Hirakawa, K. Hoshi, K. Ito, K. Gamada, Immediate effects pain in osteoarthritis: a descriptive review, Curr. Rheumatol. Rep. 20 (2018)
of leg-press exercises with tibial internal rotation on individuals with medial knee 1–10.
osteoarthritis, Physiother. Res. Int. 23 (2018), e1725. [72] A. Ghouri, P.G. Conaghan, Prospects for Therapies in Osteoarthritis, Calcified
[47] S.-L. Goh, M.S. Persson, J. Stocks, Y. Hou, J. Lin, M.C. Hall, M. Doherty, tissue international, 2020, pp. 1–12.
W. Zhang, Efficacy and potential determinants of exercise therapy in knee and hip [73] A. Ghouri, P.G. Conaghan, Treating osteoarthritis pain: recent approaches using
osteoarthritis: a systematic review and meta-analysis, Annals of physical and pharmacological therapies, Clin. Exp. Rheumatol. 37 (2019) 124–129.
rehabilitation medicine 62 (2019) 356–365. [74] A. Ghouri, P.G. Conaghan, Update on novel pharmacological therapies for
[48] C. Cheung, J.F. Wyman, U. Bronas, T. McCarthy, K. Rudser, M.A. Mathiason, osteoarthritis, Therapeutic advances in musculoskeletal disease 11 (2019),
Managing knee osteoarthritis with yoga or aerobic/strengthening exercise 1759720X19864492.
programs in older adults: a pilot randomized controlled trial, Rheumatol. Int. 37 [75] D. Amaral, A. Duarte, S. Barros, S. Cavalcanti, A. Ranzolin, V. Leite, A. Dantas,
(2017) 389–398. A. Oliveira, P. Santos, J. Silva, Assistive devices: an effective strategy in non-
[49] L. Assis, C. Tim, A. Magri, K.R. Fernandes, P.G. Vassão, A.C.M. Renno, pharmacological treatment for hand osteoarthritis—randomized clinical trial,
Interleukin-10 and collagen type II immunoexpression are modulated by Rheumatol. Int. 38 (2018) 343–351.
photobiomodulation associated to aerobic and aquatic exercises in an [76] L. Ceballos-Laita, E. Estébanez-de-Miguel, G. Martín-Nieto, E. Bueno-Gracia,
experimental model of osteoarthritis, Laser Med. Sci. 33 (2018) 1875–1882. M. Fortún-Agúd, S. Jiménez-del-Barrio, Effects of non-pharmacological
[50] C.G.D. Kurniawan, The principle of non-pharmacologic management of conservative treatment on pain, range of motion and physical function in patients
osteoarthritis, ijbs, 12 152. with mild to moderate hip osteoarthritis, A systematic review, Complementary
[51] G.K. Fitzgerald, D.K. White, S.R. Piva, Associations for change in physical and therapies in medicine 42 (2019) 214–222.
psychological factors and treatment response following exercise in knee [77] F. Rannou, J.-P. Pelletier, J. Martel-Pelletier, Efficacy and Safety of Topical
osteoarthritis: an exploratory study, Arthritis Care Res. 64 (2012) 1673–1680. NSAIDs in the Management of Osteoarthritis: Evidence from Real-Life Setting
[52] C. MacKay, G.A. Hawker, S.B. Jaglal, Qualitative study exploring the factors Trials and Surveys, Seminars in Arthritis and Rheumatism, Elsevier, 2016,
influencing physical therapy management of early knee osteoarthritis in Canada, pp. S18–S21.
BMJ open 8 (2018), e023457. [78] M. Derwich, M. Mitus-Kenig, E. Pawlowska, Orally administered
[53] C. MacKay, G.A. Hawker, S.B. Jaglal, How do physical therapists approach NSAIDs—general characteristics and usage in the treatment of
management of people with early knee osteoarthritis? A qualitative study, Phys. temporomandibular joint osteoarthritis—a narrative review, Pharmaceuticals 14
Ther. 100 (2020) 295–306. (2021) 219.
[54] N. Yıldırım, M. Filiz Ulusoy, H. Bodur, The effect of heat application on pain, [79] R. Altman, R.L. Barkin, Topical therapy for osteoarthritis: clinical and
stiffness, physical function and quality of life in patients with knee osteoarthritis, pharmacologic perspectives, PGM (Postgrad. Med.) 121 (2009) 139–147.
J. Clin. Nurs. 19 (2010) 1113–1120. [80] Z. Meng, R. Huang, Topical treatment of degenerative knee osteoarthritis, Am. J.
[55] R.M. Palmieri-Smith, A.C. Thomas, C. Karvonen-Gutierrez, M. Sowers, A clinical Med. Sci. 355 (2018) 6–12.
trial of neuromuscular electrical stimulation in improving quadriceps muscle [81] B. Nair, R. Taylor-Gjevre, A review of topical diclofenac use in musculoskeletal
strength and activation among women with mild and moderate osteoarthritis, disease, Pharmaceuticals 3 (2010) 1892–1908.
Phys. Ther. 90 (2010) 1441–1452. [82] R. Habib, K. El Zein, S. Hojeij, Hard work at home: musculoskeletal pain among
[56] Z. Wu, X. Ding, G. Lei, C. Zeng, J. Wei, J. Li, H. Li, T. Yang, Y. Cui, Y. Xiong, female homemakers, Ergonomics 55 (2012) 201–211.
Efficacy and safety of the pulsed electromagnetic field in osteoarthritis: a meta- [83] E. Maheu, F. Rannou, J.-Y. Reginster, Efficacy and Safety of Hyaluronic Acid in
analysis, BMJ open 8 (2018), e022879. the Management of Osteoarthritis: Evidence from Real-Life Setting Trials and
[57] X. Yang, H. He, W. Ye, T.A. Perry, C. He, Effects of pulsed electromagnetic field Surveys, Seminars in Arthritis and Rheumatism, Elsevier, 2016, pp. S28–S33.
therapy on pain, stiffness, physical function, and quality of life in patients with [84] A. Gigante, L. Callegari, The role of intra-articular hyaluronan (Sinovial®) in the
osteoarthritis: a systematic review and meta-analysis of randomized placebo- treatment of osteoarthritis, Rheumatol. Int. 31 (2011) 427–444.
controlled trials, Phys. Ther. 100 (2020) 1118–1131. [85] J.C. Fernandes, J. Martel-Pelletier, J.P. Pelletier, The role of cytokines in
[58] G. Gremion, D. Gaillard, P.-F. Leyvraz, B.M. Jolles, Effect of biomagnetic therapy osteoarthritis pathophysiology, Biorheology 39 (2002) 237–246.
versus physiotherapy for treatment of knee osteoarthritis: a randomized [86] F. Smeraglia, S. Barrera-Ochoa, G. Mendez-Sanchez, M.A. Basso, G. Balato,
controlled trial, J. Rehabil. Med. 41 (2009) 1090–1095. X. Mir-Bullo, Partial trapeziectomy and pyrocarbon interpositional arthroplasty
[59] X. Shi, W. Yu, T. Wang, Q. Shu, C. Wang, X. Yang, C. Liu, C. Guo, A comparison of for trapeziometacarpal osteoarthritis: minimum 8-year follow-up, J. Hand Surg.
the effects of electroacupuncture vs transcutaneous electrical nerve stimulation 45 (2020) 472–476.
for pain control in knee osteoarthritis: a protocol for network meta-analysis of [87] P. Hoff, F. Buttgereit, G.-R. Burmester, M. Jakstadt, T. Gaber, K. Andreas,
randomized controlled trials, Medicine (2019) 98. G. Matziolis, C. Perka, E. Röhner, Osteoarthritis synovial fluid activates pro-
[60] T. Maeda, H. Yoshida, T. Sasaki, A. Oda, Does transcutaneous electrical nerve inflammatory cytokines in primary human chondrocytes, Int. Orthop. 37 (2013)
stimulation (TENS) simultaneously combined with local heat and cold 145–151.
applications enhance pain relief compared with TENS alone in patients with knee [88] S. Cai, B. Ming, C. Ye, S. Lin, P. Hu, J. Tang, F. Zheng, L. Dong, Similar transition
osteoarthritis? J. Phys. Ther. Sci. 29 (2017) 1860–1864. processes in synovial fibroblasts from rheumatoid arthritis and osteoarthritis: a
[61] P.P. Alfredo, J.M. Bjordal, S.H. Dreyer, S.R.F. Meneses, G. Zaguetti, single-cell study, Journal of immunology research (2019) 2019.
V. Ovanessian, T.Y. Fukuda, W.S. Junior, R.Á.B.L. Martins, R.A. Casarotto, [89] P. Emery, T. Koncz, S. Pan, S. Lowry, Analgesic effectiveness of celecoxib and
Efficacy of low level laser therapy associated with exercises in knee osteoarthritis: diclofenac in patients with osteoarthritis of the hip requiring joint replacement
a randomized double-blind study, Clin. Rehabil. 26 (2012) 523–533. surgery: a 12-week, multicenter, randomized, double-blind, parallel-group,
[62] R. Ganji, Aromatherapy massage: a promising non-pharmacological adjuvant double-dummy, noninferiority study, Clin. Therapeut. 30 (2008) 70–83.
treatment for osteoarthritis knee pain, The Korean journal of pain 32 (2019) 133. [90] D.S. Casper, A.N. Fleischman, P.V. Papas, J. Grossman, G.R. Scuderi, J.H. Lonner,
[63] A.O. Ojoawo, O. Adesola, W.A. Wasiu Abiodun Fatai, Comparative efficacy of Unicompartmental knee arthroplasty provides significantly greater improvement
kneading massage and pulsed mode ultrasound in the management of chronic in function than total knee arthroplasty despite equivalent satisfaction for
knee osteoarthritis, European Journal of Clinical and Experimental Medicine isolated medial compartment osteoarthritis, J. Arthroplasty 34 (2019)
(2020) 275–280. 1611–1616.
[64] A.I. Perlman, A. Ali, V.Y. Njike, D. Hom, A. Davidi, S. Gould-Fogerite, C. Milak, D. [91] H. Bagga, D. Burkhardt, P. Sambrook, L. March, Longterm effects of intraarticular
L. Katz, Massage therapy for osteoarthritis of the knee: a randomized dose-finding hyaluronan on synovial fluid in osteoarthritis of the knee, J. Rheumatol. 33
trial, PLoS One 7 (2012), e30248. (2006) 946–950.
[65] M.E. Suarez-Almazor, C. Looney, Y. Liu, V. Cox, K. Pietz, D.M. Marcus, R. [92] M. Maggio, J.M. Guralnik, D.L. Longo, L. Ferrucci, Interleukin-6 in aging and
L. Street Jr., A randomized controlled trial of acupuncture for osteoarthritis of the chronic disease: a magnificent pathway, The Journals of Gerontology Series A:
knee: effects of patient-provider communication, Arthritis Care Res. 62 (2010) Biological Sciences and Medical Sciences 61 (2006) 575–584.
1229–1236. [93] Z. Zainal, A.J. Longman, S. Hurst, K. Duggan, B. Caterson, C.E. Hughes, J.
[66] D.A. Mistry, A. Chandratreya, P.Y. Lee, An update on unloading knee braces in L. Harwood, Relative efficacies of omega-3 polyunsaturated fatty acids in
the treatment of unicompartmental knee osteoarthritis from the last 10 years: a reducing expression of key proteins in a model system for studying osteoarthritis,
literature review, Surg. J. 4 (2018) e110–e118. Osteoarthritis Cartilage 17 (2009) 896–905.
[67] P. Thoumie, M. Marty, B. Avouac, A. Pallez, A. Vaumousse, L.P.T. Pipet, [94] K. Gottesdiener, T. Schnitzer, C. Fisher, B. Bockow, J. Markenson, A. Ko,
A. Monroche, N. Graveleau, A. Bonnin, C.B. Amor, Effect of unloading brace L. DeTora, S. Curtis, L. Geissler, B. Gertz, Results of a randomized, dose-ranging
treatment on pain and function in patients with symptomatic knee osteoarthritis: trial of etoricoxib in patients with osteoarthritis, Rheumatology 41 (2002)
the ROTOR randomized clinical trial, Sci. Rep. 8 (2018) 1–9. 1052–1061.
[68] M. Khosravi, T. Babaee, A. Daryabor, M. Jalali, Effect of Knee Braces and Insoles [95] A.K. Wann, J. Mistry, E.J. Blain, A.T. Michael-Titus, M.M. Knight,
on Clinical Outcomes of Individuals with Medial Knee Osteoarthritis: A Eicosapentaenoic acid and docosahexaenoic acid reduce interleukin-1β-mediated
Systematic Review and Meta-Analysis, Assistive Technology, 2021, pp. 1–17. cartilage degradation, Arthritis Res. Ther. 12 (2010) 1–9.
[69] H.L. Siebers, J. Eschweiler, J. Pinz, M. Tingart, B. Rath, The effect of a knee brace [96] J.K. Roush, A.R. Cross, W.C. Renberg, C.E. Dodd, K.A. Sixby, D.A. Fritsch, T.
in dynamic motion—an instrumented gait analysis, PLoS One 15 (2020), A. Allen, D.E. Jewell, D.C. Richardson, P.S. Leventhal, Evaluation of the effects of
e0238722. dietary supplementation with fish oil omega-3 fatty acids on weight bearing in
dogs with osteoarthritis, J. Am. Vet. Med. Assoc. 236 (2010) 67–73.

8
M. Maqbool et al. Annals of Medicine and Surgery 72 (2021) 103077

[97] D.A. Fritsch, T.A. Allen, C.E. Dodd, D.E. Jewell, K.A. Sixby, P.S. Leventhal, [125] J. Wang, Efficacy and safety of adalimumab by intra-articular injection for
J. Brejda, K.A. Hahn, A multicenter study of the effect of dietary supplementation moderate to severe knee osteoarthritis: an open-label randomized controlled trial,
with fish oil omega-3 fatty acids on carprofen dosage in dogs with osteoarthritis, J. Int. Med. Res. 46 (2018) 326–334.
J. Am. Vet. Med. Assoc. 236 (2010) 535–539. [126] F.P. Kroon, A.C. Bay-Jensen, R. Wittoek, G. Verbruggen, J.S. Smolen,
[98] L. Knott, N. Avery, A. Hollander, J. Tarlton, Regulation of osteoarthritis by M. Kloppenburg, R. Ramonda, Etanercept therapy leads to reductions in matrix
omega-3 (n-3) polyunsaturated fatty acids in a naturally occurring model of metalloproteinase-3 in patients with erosive hand osteoarthritis, Scand. J.
disease, Osteoarthritis Cartilage 19 (2011) 1150–1157. Rheumatol. 49 (2020) 167–168.
[99] N. Caturla, L. Funes, L. Pérez-Fons, V. Micol, A randomized, double-blinded, [127] M. Loef, F.P. Kroon, S.A. Bergstra, J.A. van der Pol, W.F. Lems, P.J. Kerstens, C.
placebo-controlled study of the effect of a combination of lemon verbena extract F. Allaart, M. Kloppenburg, TNF inhibitor treatment is associated with a lower
and fish oil omega-3 fatty acid on joint management, J. Alternative Compl. Med. risk of hand osteoarthritis progression in rheumatoid arthritis patients after 10
17 (2011) 1051–1063. years, Rheumatology 57 (2018) 1917–1924.
[100] K. Yokes, Essential Fatty Acids in Pain Management, Pain, Springer2019, pp. 335- [128] S.R. Kingsbury, P. Tharmanathan, A. Keding, S.J. Ronaldson, A. Grainger, R.
338. J. Wakefield, C. Arundel, F. Birrell, M. Doherty, T. Vincent, Hydroxychloroquine
[101] U. Akbar, M. Yang, D. Kurian, C. Mohan, Omega-3 fatty acids in rheumatic effectiveness in reducing symptoms of hand osteoarthritis: a randomized trial,
diseases: a critical review, J. Clin. Rheumatol. 23 (2017) 330–339. Ann. Intern. Med. 168 (2018) 385–395.
[102] S. Kumar, G.J. Dobos, T. Rampp, The significance of Ayurvedic medicinal plants, [129] K. Grothe, K. Flechsenhar, T. Paehler, O. Ritzeler, J. Beninga, J. Saas,
Journal of evidence-based complementary & alternative medicine 22 (2017) M. Herrmann, K. Rudolphi, IκB kinase inhibition as a potential treatment of
494–501. osteoarthritis–results of a clinical proof-of-concept study, Osteoarthritis Cartilage
[103] V. Remya, M.J. Alex, A. Thomas, Quality Control of Ayurvedic Medicines, 25 (2017) 46–52.
Ayurveda in the New Millennium, CRC Press2020, pp. 71-100. [130] T.J. Schnitzer, R. Easton, S. Pang, D.J. Levinson, G. Pixton, L. Viktrup,
[104] B.N. Lindler, K.E. Long, N.A. Taylor, W. Lei, Use of herbal medications for I. Davignon, M.T. Brown, C.R. West, K.M. Verburg, Effect of tanezumab on joint
treatment of osteoarthritis and rheumatoid arthritis, Medicines 7 (2020) 67. pain, physical function, and patient global assessment of osteoarthritis among
[105] A. Mishra, L. Batham, S. Verma, S. Mishra, V. Shrivastava, Management of the patients with osteoarthritis of the hip or knee: a randomized clinical trial, Jama
symptoms associated with osteoarthritis of the knee through an integrated 322 (2019) 37–48.
approach including yagya therapy, Interdisciplinary Journal of Yagya Research 2 [131] E. Krupka, G.-L. Jiang, C. Jan, Efficacy and safety of intra-articular injection of
(2019) 29–37. tropomyosin receptor kinase A inhibitor in painful knee osteoarthritis: a
[106] R. Kaul-Ghanekar, P. Raina, Potential of nutraceuticals and medicinal plants in randomized, double-blind and placebo-controlled study, Osteoarthritis Cartilage
the management of osteoarthritis, Acta Biologica Indica 1 (2012) 27–46. 27 (2019) 1599–1607.
[107] C.T. Peterson, K. Denniston, D. Chopra, Therapeutic uses of triphala in ayurvedic [132] R.M. Stevens, J. Ervin, J. Nezzer, Y. Nieves, K. Guedes, R. Burges, P.D. Hanson, J.
medicine, J. Alternative Compl. Med. 23 (2017) 607–614. N. Campbell, Randomized, double-blind, placebo-controlled trial of intraarticular
[108] S.J. Snelling, A. Forster, S. Mukherjee, A.J. Price, R.C. Poulsen, The chondrocyte- trans-capsaicin for pain associated with osteoarthritis of the knee, Arthritis &
intrinsic circadian clock is disrupted in human osteoarthritis, Chronobiol. Int. 33 Rheumatology 71 (2019) 1524–1533.
(2016) 574–579. [133] P. Manitpisitkul, C.M. Flores, J.A. Moyer, G. Romano, K. Shalayda, K. Tatikola, J.
[109] K.B. Harikumar, A.M. Jesil, M.C. Sabu, R. Kuttan, A preliminary assessment of the S. Hutchison, A.J. Mayorga, A multiple-dose double-blind randomized study to
acute and subchronic toxicity profile of phase2: an α-amylase inhibitor, Int. J. evaluate the safety, pharmacokinetics, pharmacodynamics and analgesic efficacy
Toxicol. 24 (2005) 95–102. of the TRPV1 antagonist JNJ-39439335 (mavatrep), Scandinavian journal of pain
[110] M. Rasool, E. Sabina, Antiinflammatory effect of the Indian Ayurvedic herbal 18 (2018) 151–164.
formulation Triphala on adjuvant-induced arthritis in mice, Phytother Res.: An [134] Y. Jin, C. Smith, D. Monteith, R. Brown, A. Camporeale, T. McNearney, M. Deeg,
International Journal Devoted to Pharmacological and Toxicological Evaluation E. Raddad, N. Xiao, A. de la Peña, CGRP blockade by galcanezumab was not
of Natural Product Derivatives 21 (2007) 889–894. associated with reductions in signs and symptoms of knee osteoarthritis in a
[111] P. Sharma, M. Yelne, T. Dennis, A. Joshi, K. Billore, Database on Medicinal Plants randomized clinical trial, Osteoarthritis Cartilage 26 (2018) 1609–1618.
Used in Ayurveda, 2000. [135] L. Rovati, N. Brambilla, T. Blicharski, J. Connell, C. Vitalini, A. Bonazzi,
[112] R.R. Parekar, K.K. Dash, P.A. Marathe, A.A. Apte, N.N. Rege, Evaluation of Anti- G. Giacovelli, F. Girolami, M. D’Amato, Efficacy and safety of the first-in-class
inflammatory Activity of Root Bark of Clerodendrum Phlomidis in Experimental imidazoline-2 receptor ligand CR4056 in pain from knee osteoarthritis and
Models of Inflammation, 2012. disease phenotypes: a randomized, double-blind, placebo-controlled phase 2 trial,
[113] S. Grässel, D. Muschter, Recent Advances in the Treatment of Osteoarthritis, Osteoarthritis Cartilage 28 (2020) 22–30.
F1000Research, 2020, p. 9. [136] C.-H. Lu, C.-H. Chung, C.-H. Lee, C.-H. Hsieh, Y.-J. Hung, F.-H. Lin, C.-H. Tsao, P.-
[114] D. Tonge, M. Pearson, S. Jones, The hallmarks of osteoarthritis and the potential S. Hsieh, W.-C. Chien, Combination COX-2 inhibitor and metformin attenuate rate
to develop personalised disease-modifying pharmacological therapeutics, of joint replacement in osteoarthritis with diabetes: a nationwide, retrospective,
Osteoarthritis Cartilage 22 (2014) 609–621. matched-cohort study in Taiwan, PLoS One 13 (2018), e0191242.
[115] M.C. Hochberg, A. Guermazi, H. Guehring, A. Aydemir, S. Wax, P. Fleuranceau- [137] F. Eymard, C. Parsons, M.H. Edwards, F. Petit-Dop, J.-Y. Reginster, O. Bruyère,
Morel, A.R. Bihlet, I. Byrjalsen, J.R. Andersen, F. Eckstein, Effect of intra-articular X. Chevalier, C. Cooper, P. Richette, Statin use and knee osteoarthritis
sprifermin vs placebo on femorotibial joint cartilage thickness in patients with progression: results from a post-hoc analysis of the SEKOIA trial, Joint Bone Spine
osteoarthritis: the FORWARD randomized clinical trial, Jama 322 (2019) 85 (2018) 609–614.
1360–1370. [138] K. Michaëlsson, L. Lohmander, A. Turkiewicz, A. Wolk, P. Nilsson, M. Englund,
[116] C.H. Evans, V.B. Kraus, L.A. Setton, Progress in intra-articular therapy, Nat. Rev. Association between statin use and consultation or surgery for osteoarthritis of
Rheumatol. 10 (2014) 11. the hip or knee: a pooled analysis of four cohort studies, Osteoarthritis Cartilage
[117] W.E. Van Spil, O. Kubassova, M. Boesen, A.-C. Bay-Jensen, A. Mobasheri, 25 (2017) 1804–1813.
Osteoarthritis phenotypes and novel therapeutic targets, Biochem. Pharmacol. [139] J.N. Katz, B.E. Earp, A.H. Gomoll, Surgical management of osteoarthritis, Arthritis
165 (2019) 41–48. Care Res. 62 (2010) 1220.
[118] E. Vaysbrot, M. Osani, M.-C. Musetti, T. McAlindon, R. Bannuru, Are [140] B.J. McGrory, K.L. Weber, D.S. Jevsevar, K. Sevarino, Surgical management of
bisphosphonates efficacious in knee osteoarthritis? A meta-analysis of osteoarthritis of the knee: evidence-based guideline, J. Am. Acad. Orthop. Surg.
randomized controlled trials, Osteoarthritis Cartilage 26 (2018) 154–164. 24 (2016) e87–e93.
[119] R.E. Miller, J.A. Block, A.-M. Malfait, What is new in pain modification in [141] S. Goodman, A. Yee, S. Paget, Expert Guide to Rheumatology, American College
osteoarthritis? Rheumatology 57 (2018) iv99–iv107. of Physicians, Philadelphia, PA, 2005, pp. 269–283.
[120] P.G. Conaghan, M.A. Bowes, S.R. Kingsbury, A. Brett, G. Guillard, B. Rizoska, [142] S.F.S. Clair, C. Higuera, V. Krebs, N.A. Tadross, J. Dumpe, W.K. Barsoum, Hip and
N. Sjögren, P. Graham, Å. Jansson, C. Wadell, Disease-modifying effects of a novel knee arthroplasty in the geriatric population, Clin. Geriatr. Med. 22 (2006)
cathepsin k inhibitor in osteoarthritis: a randomized controlled trial, Ann. Intern. 515–533.
Med. 172 (2020) 86–95. [143] A. Kirkley, T.B. Birmingham, R.B. Litchfield, J.R. Giffin, K.R. Willits, C.J. Wong,
[121] X. Chevalier, P. Goupille, A. Beaulieu, F. Burch, W. Bensen, T. Conrozier, B.G. Feagan, A. Donner, S.H. Griffin, L.M. D’Ascanio, A randomized trial of
D. Loeuille, A. Kivitz, D. Silver, B. Appleton, Intraarticular injection of anakinra in arthroscopic surgery for osteoarthritis of the knee, N. Engl. J. Med. 359 (2008)
osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo- 1097–1107.
controlled study, Arthritis Care Res. 61 (2009) 344–352. [144] J.N. Katz, R.H. Brophy, C.E. Chaisson, L. De Chaves, B.J. Cole, D.L. Dahm, L.
[122] S.B. Cohen, S. Proudman, A.J. Kivitz, F.X. Burch, J.P. Donohue, D. Burstein, Y.- A. Donnell-Fink, A. Guermazi, A.K. Haas, M.H. Jones, Surgery versus physical
N. Sun, C. Banfield, M.S. Vincent, L. Ni, A randomized, double-blind study of therapy for a meniscal tear and osteoarthritis, N. Engl. J. Med. 368 (2013)
AMG 108 (a fully human monoclonal antibody to IL-1R1) in patients with 1675–1684.
osteoarthritis of the knee, Arthritis Res. Ther. 13 (2011) 1–12. [145] P.Y. Shirley, D.J. Hunter, Managing osteoarthritis, Aust. Prescr. 38 (2015) 115.
[123] R.M. Fleischmann, H. Bliddal, F.J. Blanco, T.J. Schnitzer, C. Peterfy, S. Chen, [146] K. Rönn, N. Reischl, E. Gautier, M. Jacobi, Current Surgical Treatment of Knee
L. Wang, S. Feng, P.G. Conaghan, F. Berenbaum, A phase II trial of lutikizumab, Osteoarthritis, Arthritis, 2011, 2011.
an anti–interleukin-1α/β dual variable domain immunoglobulin, in knee [147] N. Reischl, E. Gautier, M. Jacobi, Current Surgical Treatment of Knee
osteoarthritis patients with synovitis, Arthritis & rheumatology 71 (2019) Osteoarthritis, Arthritis, 2011 (20901984).
1056–1069. [148] M. Wang, E.R. Sampson, H. Jin, J. Li, Q.H. Ke, H.-J. Im, D. Chen, MMP13 is a
[124] D. Aitken, L.L. Laslett, F. Pan, I.K. Haugen, P. Otahal, N. Bellamy, P. Bird, critical target gene during the progression of osteoarthritis, Arthritis Res. Ther. 15
G. Jones, A randomised double-blind placebo-controlled crossover trial of (2013) 1–11.
HUMira (adalimumab) for erosive hand OsteoaRthritis–the HUMOR trial, [149] P. Krzeski, C. Buckland-Wright, G. Bálint, G.A. Cline, K. Stoner, R. Lyon, J. Beary,
Osteoarthritis Cartilage 26 (2018) 880–887. W.S. Aronstein, T.D. Spector, Development of musculoskeletal toxicity without

9
M. Maqbool et al. Annals of Medicine and Surgery 72 (2021) 103077

clear benefit after administration of PG-116800, a matrix metalloproteinase [155] T. Funck-Brentano, W. Bouaziz, C. Marty, V. Geoffroy, E. Hay, M. Cohen-Solal,
inhibitor, to patients with knee osteoarthritis: a randomized, 12-month, double- Dkk-1–Mediated inhibition of Wnt signaling in bone ameliorates osteoarthritis in
blind, placebo-controlled study, Arthritis Res. Ther. 9 (2007) 1–11. mice, Arthritis & rheumatology 66 (2014) 3028–3039.
[150] K. Holmbeck, P. Bianco, J. Caterina, S. Yamada, M. Kromer, S.A. Kuznetsov, [156] X. Cai, S. Yuan, Y. Zeng, C. Wang, N. Yu, C. Ding, New trends in pharmacological
M. Mankani, P.G. Robey, A.R. Poole, I. Pidoux, MT1-MMP-deficient mice develop treatments for osteoarthritis, Front. Pharmacol. 12 (2021) 701.
dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate [157] A. Latourte, M. Kloppenburg, P. Richette, Emerging pharmaceutical therapies for
collagen turnover, Cell 99 (1999) 81–92. osteoarthritis, Nat. Rev. Rheumatol. 16 (2020) 673–688.
[151] P. Chen, S. Zhu, Y. Wang, Q. Mu, Y. Wu, Q. Xia, X. Zhang, H. Sun, J. Tao, H. Hu, [158] M. Chen, Y. Li, X. Huang, Y. Gu, S. Li, P. Yin, L. Zhang, P. Tang, Skeleton-
The amelioration of cartilage degeneration by ADAMTS-5 inhibitor delivered in a vasculature chain reaction: a novel insight into the mystery of homeostasis, Bone
hyaluronic acid hydrogel, Biomaterials 35 (2014) 2827–2836. Research 9 (2021) 1–20.
[152] F. Echtermeyer, J. Bertrand, R. Dreier, I. Meinecke, K. Neugebauer, M. Fuerst, Y. [159] A.R. Zorzi, Uso de células-tronco mesenquimais do tecido adiposo humano em um
J. Lee, Y.W. Song, C. Herzog, G. Theilmeier, Syndecan-4 regulates ADAMTS-5 modelo experimental de reparo da cartilagem articular= Human adipose tissue
activation and cartilage breakdown in osteoarthritis, Nat. Med. 15 (2009) mesenchymal stem cells use in a cartilage repair experimental model, 2015.
1072–1076. [160] M. Ondresik, F.R. Azevedo Maia, A. da Silva Morais, A.C. Gertrudes, A.H. Dias
[153] G. Zhen, C. Wen, X. Jia, Y. Li, J.L. Crane, S.C. Mears, F.B. Askin, F.J. Frassica, Bacelar, C. Correia, C. Goncalves, H. Radhouani, R. Amandi Sousa, J.M. Oliveira,
W. Chang, J. Yao, Inhibition of TGF-β signaling in mesenchymal stem cells of Management of knee osteoarthritis. Current status and future trends, Biotechnol.
subchondral bone attenuates osteoarthritis, Nat. Med. 19 (2013) 704. Bioeng. 114 (2017) 717–739.
[154] R.J. Lories, M. Corr, N.E. Lane, To Wnt or not to Wnt: the bone and joint health
dilemma, Nat. Rev. Rheumatol. 9 (2013) 328.

10