Bone and joint

Functions:
- Support and locomotion
- Protection of internal organs
- Homeostasis and synthesis of minerals
Types of bone cells:
o Osteoprogenitor cells: derived from the periosteum and endosteum.
Lead to osteoblasts.
o Osteoblasts: important for the synthesis of bone
o Osteocytes: mature bone cells that are trapped within lacunae
o Osteoclasts: responsible for bone resorption
The bone matrix is composed of repeating osteons and can be divided into
two parts:
• Organic portion – composed of collagen and proteins that provide tensile
strength.
• Inorganic portion (minerals) – calcium phosphate crystals that provide
rigidity.
Formation of embryonic bones
Intramembranous ossification (no cartilage involved)
o Mesenchymal cells directly secrete collagen and are turned into osteoblasts. Calcium phosphate crystals
are laid down within the matrix. Osteoblasts become ‘trapped’ within the crystals and become
osteocytes. Mostly applies to flat bone development in the skull.
Endochondral ossification (built from hyaline cartilage)
o Mesenchymal cells first differentiate into chondrocytes, which then lay out a hyaline cartilage model in
the shape of the future bone. ‘Centers of ossification’ arise within the model, chondrocytes and lacunae
enlarge, leaving thin strands of cartilage matrix. The thin strands of cartilage matrix accumulate calcium
phosphate crystal deposits (calcified cartilage matrix). The enlarged chondrocytes undergo apoptosis (cell
death), space is invaded by blood vessels and osteoprogenitor cells follow, giving rise to osteoblasts that
congregate on the surface of the calcified cartilage matrix. The osteoblasts produce a bone matrix,
consisting of randomly orientated collagen and proteins. Applies to majority of developing bones –
bones of extremities, vertebral column, pelvis.
Length growth of the bone:
Growth in the length of the bone, occurs in the epiphyseal plates, under control of growth hormone
(somatotropin) secreted by the pituitary gland, initiating localized production of insulin-like growth factor 1
(somatomedin), which stimulates chondrocytes in the zone of proliferation to undergo mitotic divisions.
The epiphyseal plate has three distinct layers:
1. Zone of proliferation – the epiphysis side of the plate. Columns of chondrocytes undergo mitotic divisions and
secrete cartilaginous matrix.
2. Zone of maturation – next zone towards the diaphysis. Chondrocytes have stopped dividing and become
enlarged.
3. Zone of hypertrophy (zone of provisional calcification) – further enlargement and vacuolization of
chondrocytes. Cartilaginous matrix becomes calcified.
Diameter growth of the bone:
Growth in diameter of long bones occur by deposition of new bone by osteoblasts within the outer periosteum
and accompanied resorption of older bone by osteoclast in the interior of the shaft.
- This allows the increase in bone diameter to keep pace with the increase in length (important for
biomechanics). It also allows for bone marrow expansion (important for haematopoiesis).
Bone remodeling is the process by which micro-fractures within the bone, caused by internal and external
force loads (stress loads), are replaced with new bone to maintain overall structural integrity (otherwise the
micro-fractures will accumulate and result in failure of the bone). Remodeling is undertaken by bone
remodeling units:
1. Activation – identification of the site to be remodeled, osteoblasts lining the bone surface retract, exposing
the bone matrix, allowing osteoclasts to bind to the exposed site.
2. Resorption – osteoclasts release acids and proteolytic enzymes (protein degrading) dissolving the bone
matrix. Forms a depression and leaves.
3. Reversal – osteoblasts move back along the surface and into the vacated depression.
4. Formation – osteoblasts deposit new osteoid in discrete layers of lamellae, collagen and proteins.
Bone fracture repair:
A serious bone fracture tears the periosteum and endosteum, severs blood vessels, causing blood clots to form.
Lack of blood flow then causes localized necrosis and death of osteocytes.
- Release of proinflammatory cytokines (a signaling molecule) attract phagocytes to remove blood clots and
some of the necrotic tissue.
- Intact periosteum and endosteum surrounding the fracture contain osteoprogenitor cells that give rise to
chondrocytes that proliferate and form cartilage to bridge the broken ends.
- Chondrocytes hypertrophy and undergo apoptosis, causing the cartilage matrix to calcify and blood vessels
to invade. Osteoprogenitor cells follow and give rise to osteoblasts that congregate on the surface of the
calcified cartilage matrix. Osteoblasts lay down woven bone onto the cartilage and a callus forms a complete
bridge across the bridge.
- The woven bone is then resorbed and replace by true lamellar bone beginning from the existing healthy
bone and moving inwards.
- Eventually, the callus is resorbed entirely, and the bone is remodeled to its original shape.
Cartilage
Cartilage contains chondrocytes that produce a matrix of collagen (predominantly type II, fibrous protein) and elastin
(elastic protein), often enclosed within the perichondrium. Cartilage is non-innervated and avascular. Relatively low O2
and CO2 exchange rates and nutrient/waste exchange rates. Also low in metabolic requirements.
Intermittent pumping action of weight-bearing and joint motion provides convective flow (bulk flow) that facilitates
diffusion.
Three types of cartilage can be distinguished based on the composition of the amorphous matrix:
1. Hyaline cartilage (articular)
o Larynx, tracheal rings, joint surfaces and epiphyseal plates in long bones of young animals
o Model which true bone tissue is later formed in embryonic and fetal development
o At joints it reduces friction, allows weight-bearing, and absorbs shock
o In young it has the capacity to repair, but loses much of that capacity with cessation of bone growth
1. Elastic cartilage
o External ear and epiglottis
o Functions to provide shape and support
2. Fibrous cartilage (fibrocartilage)
o Intervertebral discs, symphysis (fusion between two bones)
o Functions to provide rigidity and absorb shock
Synovial joint
A synovial membrane (synovium) surrounds the whole joint and contains the synovial fluid
lubricant within the synovial capsule. The synovial membrane has no basement membrane.
- Exhibits folds that project into joint cavity.
- Varies in thickness and can regenerate if damaged.
The synovial fluid is an ultra-filtrate of plasma with the addition of hyaluronic acid and
lubricin (synthesized by the synoviocytes).
- Exchange of gases and solutes likely facilitated by the lack of a basement membrane.
- Starling forces govern the exchange of fluids (balance between the hydrostatic pressure
gradient and oncotic pressure gradient).
- Glucose transport is facilitated
Endocrine control of Ca2+
The blood plasma calcium concentration of the carotid artery is monitored by parathyroid glands.
• If blood plasma calcium exceeds normal range, the animal is in a state of hypercalcemia. Can lead to
soft tissue calcium deposit.
• If blood plasma calcium is below normal range, the animal is in a state of hypocalcemia. Leads to weak
bones and rickets.
Hypocalcemia can also induce tetany (hyper-excitability of the nervous system, due to a decrease in
membrane potential difference, leading closer to threshold).
Hypocalcemia can lead to milk fever manifest as reduced muscle force – calcium influx into nerve’s terminal
end stimulate acetylcholine-containing vesicles to fuse and release to muscle fiber, exacerbated (worsened) by
hypermagnesemia which further competitively inhibits calcium entry).

Calcium can leave blood plasma via: Calcium can enter blood plasma via:
1. Bone formation 1. Bone resorption
2. Lactation and milk production, eggshell 2. Intestinal uptake, dietary calcium
3. Digestive secretions, sweat, urine 3. Kidneys, reabsorption of filtered calcium
1. Parathyroid hormone
Secreted by the parathyroid glands in response to hypocalcemia, to increase extracellular calcium levels.
If hypocalcemia is minor and acute, restoration of extracellular calcium levels can be achieved by the action of
PTH to:
- Increase renal calcium reabsorption
- Increase osteocytic osteolysis whereby calcium is pumped from lacunae fluid into non-bone
extracellular fluid.
o If hypocalcemia is substantial and chronic (due to diet or lactation), restoration of extracellular calcium
levels requires the prolonged action of PTH to increase:
- Intestinal calcium absorption (via calcitriol)
- Osteoclastic osteolysis whereby continued secretion of PTH activity increases activity of osteoclasts to
resorb bones.
The mechanism is indirect, in that PTH actually binds to receptors on the osteoblasts to move aside to expose
bone matrix for the osteoclasts to move in. This increases the number of sites undergoing activation and
resorption phases of bone remodeling.
o PTH also prevents osteoblasts from laying down new bone matrix within the resorption depression created
by the osteoclasts.
Calcitriol
Calcitriol (1,25-dihydroxyvitamin D) – normally synthesized in the liver and kidneys, released in
response to hypocalcemia, to increase extracellular calcium levels. It is derived from vitamin D.
Vitamin D itself is not a hormone. It is derived to 25-hydroxyvitamin D in the liver, which is derived
into calcitriol (1,25-dihydroxyvitamin D) in the kidneys.
o Calcitriol works with parathyroid hormone and is activated during hypocalcemia. The role of
calcitriol in calcium homeostasis is primarily indirect, as it is synthesized in the kidneys and
controlled by PTH.
o Calcium uptake occurs passively across any part of the digestive tract, but calcitriol increase:
- The active uptake of calcium primarily across the small intestine. Calcitriol signals the
synthesis and opening of calcium transport channel proteins in the epithelium, allowing
entry of Ca2+ into the cytosol. Calcium-binding proteins then capture Ca2+ at the apical side
and ferries it to the basal side, where Ca2+-ATPase pumps it against gradient into the
extracellular fluid.
- Increases osteoclastic osteolysis activity
Calcitonin
Calcitonin – secreted by C-cells within the thyroid gland, in response to
hypercalcemia, to decrease extracellular calcium levels.
o Calcitonin decreases the plasma calcium concentration by:
- Acting directly on the osteoclasts to inhibit bone resorption (decreases calcium
secretion)
- Inhibiting renal calcium reabsorption (increases loss in urine)
Endocrine control of phosphate
Almost all phosphate in the animal is combined with oxygen to form the phosphate anion PO43-.
• If blood plasma phosphate levels exceed the normal levels, the animal is in a state of
hyperphosphatemia.
• If blood plasma phosphate levels are below the normal levels, the animals is in a state of
hypophosphatemia.
- Hypophosphatemia can cause pica (abnormal appetite with particular desire for soil, flesh and bones)
- Hypophosphatemia can also cause the failure of bones to mineralize, much like hypocalcemia, leading
to rickets in growing animals and osteomalacia in adult animals.
1. Calcitriol is the key hormone in homeostasis of phosphate levels. It is released in response to
hypophosphatemia, to increase extracellular phosphate levels. Low levels of blood plasma phosphate
directly stimulate the production of calcitriol in the kidneys, which then increases the active transport of
phosphate across the small intestine.
2. Parathyroid hormone is released during hypocalcemia. PTH can however also increase the renal and
salivary excretion of phosphorus.
3. Hypocalcemic animals are thus also at risk of becoming hypophosphatemic.