 Guided by:

* Dr.A.Loomba
(H.O.D-Orthodontics)

* Dr.J.Manuel

 Presented by:
* Jitendra Bhagchandani

P.G – 1st Year

Dept. of Orthodontics &
Dentofacial Orthopedia
 Hypothesis – an assumption not proved by
experiment.
 A conclusion drawn before all the facts are
established and tentatively accepted.

 Theory – a supposition or an assumption

based on certain evidence but lacking
scientific proof
 Paradigms – not only constellations of beliefs,
values and techniques shared by members
of a given community but also concrete
models that can serve as a basis for solving
remaining problems
 THE GENETIC PARADIGM
 BRODIE ,assumed facial configuration under
genetic control

 Researches focused on growth sites for this

control: the sutures ,craniofacial cartilages
and periosteum

 Assumption made that cartilages and facial

sutures under genetic control and brain
determined the vault dimensions
 In 1940’s events reflecting changing ideas about
dominant genetic paradigm :

1) Marked increase in use of animals in craniofacial

research
2) Introduction of jaw and facial electromyography
3) Other developments included the use of
radioopaque implants,vital dyes & in vivo,in vitro
transplantations
 Functional Paradigm
 Rise of functional paradigm was when Melvin
Moss adopted van der Klauuw’s ideas ; published
a paper in American Journal of physical
anthropology in 1960 and called it the “functional
matrix hypothesis”. (Moss & Young)

 Moss suggested skeletal tissues were passive and

under direct control of functional components to
which craniofacial skeleton adapted.
 It focused on craniofacial growth from
exactly opposite view as genomic paradigm.

 Emphasized the epigenetic interaction of

intrinsic and extrinsic factors that result in
variation in craniofacial form.

 Also placed emphasis on potential of

modification of craniofacial growth & form
using principles of orthodontics and
dentofacial orthopedics
 EVOLUTION
OF
FUNCTIONAL MATRIX
HYPOTHESIS
 The skull growth hypothesis formulated by Scott
(1953) proposed cartilaginous growth centres
with intrinsic genetic control
 Craniometric & Cephalometric studies (Fuller and
West) revealed that the genetic expression was
inadequate to explain the complexities of
craniofacial growth

 Then emerged the concepts of yet another growth

centre which included condylar cartilages
 Were discarded either on experimental basis
(Durkin et al) or remained controversial
 By the late 1960’s there was an increase in
understanding and acceptance of the
important role played by physical expansion
of brain and orbital contents

 Van der Klaauw (1945)- Introduced the term

“FUNCTIONAL COMPONENTS”

 Moss was greatly influenced by van der

klaauw’s concept and undertook the
functional analysis
 The genetic, sutural and cartilaginous
growth were relegated from a dominant
intrinsically regulated entity to an
accomodative role.

 Evolutionary changes in the form of bones

were said to be secondary manifestations of
primary changes in the related soft
tissue,such as muscles that form the
“Functional matrices”
 In essence:
Head and neck are stated to consist of
a no.of relatively independent but integrated
functions such as:
digestion
respiration
vision
neural integration
 Each of the function is carried out by a
“FUNCTIONAL CRANIAL COMPONENT”
comprising of 2 parts”
 All the soft tissues to carry out function (Functional
matrix)
 To support/ protect the matrix (Skeletal unit)
FUNCTIONAL MATRIX
HYPOTHESIS
 The orthodontic specialty recently became
aware of this analytical technique (1969),
with particular interest being expressed in
the derivative concept of the functional
matrix

 The present review first defines the two

basic types of functional matrices (periosteal
and capsular) and then demonstrates their
differing and yet complementary roles as the
primary morphogenetic agencies in skeletal
tissue growth
 Functional cranial analysis
 Operationally, the head is a region within which
certain functions occur

 Every function is completely carried out by a

functional cranial component

 Each such component, in turn, is composed of two

parts:
(1) a functional matrix which actually carries out the
function
(2) a skeletal unit whose biomechanical role is to
protect and/or support its specific functional matrix
 CLASSIC STATEMENT- 1981
 Data demonstrate that all growth changes
in the size, shape, and spatial position
and, indeed, the very maintenance in
being,
of all skeletal units are always secondary
to
temporarily primary changes in their
specific functional matrices
 Functional Cranial Component

Functional Matrices Skeletal unit

Periosteal Capsular Macro Micro

(teeth,muscles) (orofacial, (endocranial (coronoid,
neurocranial) surface of angular)
calvaria)
SKELETAL UNIT
 May be composed variably of
1) Bone
2) Cartilage
3) Tendinous tissues

 They are not the equivalents of the

"bones" of formal, classic osteology.
 Microskeletal units
 When such a "bone" consists of a number of
skeletal units, e.g. both the maxilla and the
mandible are formed of a number of such
contiguous microskeletal units.
 Macroskeletal unit
 When adjoining portions of a number of
neighboring "bones" are united to function
as a single cranial component.
E.g. The endocranial surface
of the calvaria.
 In the mandible we distinguish easily:
 A coronoid microskeletal unit related to the
functional demands of the temporalis muscle

 An angular microskeletal unit related to the

activity of both the masseter and medial
pterygoid muscles

 An alveolar unit related to the presence and

position of teeth
 INFERENCE:
 To a variable extent, contiguous
microskeletal units are independent of each
other

 This implies that changes in the size, shape,

or position of the coronoid process as a
result of primary changes in temporalis
muscle are relatively independent of such
changes in other mandibular microskeletal
units
FUNCTIONAL
MATRIX
 The term functional matrix is by no means
equivalent to what is commonly understood as
"soft tissues," i.e. muscles, glands, nerves,
vessels, fat, etc., although all of these are
obviously included within the concept
INFACT
 Teeth are also a functional matrix

 Most orthodontic therapy is based firmly on the

fact that when this functional matrix grows or is
moved, the related skeletal unit (the alveolar
bone) responds appropriately to this
morphogenetic primary demand
 Two basic types of functional matrix:
 Periosteal matrices
 Capsular matrices

 Both the matrices most clearly indicate the

sites of their activity
 Periosteal matrices
 The coronoid process first arises within the
earlier formed anlage of the temporalis
muscle whose contractile abilities are well
developed in prenatal stages

 Its subsequent growth (coronoid) also

occurs within the muscular matrix
 The fibrous noncontractile portion of the
temporalis muscle is attached to the
coronoid process in a variable manner

 Indirectly to the outer fibrous layer of the

periosteum for the most part

 To a slight degree, by insertion into skeletal

tissue itself,at a relatively late postnatal age.
 INFERENCE:
 There exist considerable mutually
confirmatory data showing that :

 Experimental removal of the mammalian

temporalis muscle, or its denervation,
invariably results in an actual diminution
of coronoid process size and shape or,
indeed, in its total disappearance
  Similarly, it is well established that
functional hypertrophy or hyperactivity
of the temporalis muscle is productive of
increased coronoid process size and
also alteration of its shape
 NOTE :
 Finally, it is established also that
experimental or clinical alteration of the
muscles attaching to the other mandibular
ramal skeletal units can produce
compensatory changes in temporalis muscle
function.

 This will equally well change the size and

shape of the coronoid process in proportion
to the degree of muscular imbalance
produced
 The fundamental point
 The total growth changes in all aspects
of coronoid process form
(size and shape)
are at all times a direct and compensatory
response to the morphogenetically and
temporarily prior demands of the
temporalis muscle function.
 All responses of the osseous portions of
skeletal units to periosteal matrices are
brought about by:

 The complementary and interrelated

process of osseous deposition and
resorption.

 The resultant effect of all such skeletal unit

responses to periosteal matrices is to alter
their size and/or their shape
 Muscles are an excellent example of
periosteal functional matrices

ALTHOUGH

 Blood vessels, nerves, and glands produce

morphologic changes in their related
skeletal units in a completely homologous
manner
 These same effects can also serve to alter the
relative proportions between the contiguous
skeletal units found within one of the "bones" of
formal osteology

 In this manner, the changes of the size and shape

of the human mandible, in the formal osteologic
sense, can be comprehended in a general way

 The net backward displacement (or repositioning)

of the several contiguous microskeletal units
forming the ramus during growth is a good
example of such an alteration
 Capsular matrices
 All the functional cranial components (functional
matrices plus skeletal units) are organized in the form
of cranial capsules

 At this time to consider only two cranial capsules:

 the neurocranial
 the orofacial

 Each of these capsules is an envelope which contains

a series of functional cranial components (skeletal units
plus their related functional matrices) which, as a
whole, are sandwiched in between two covering layers.
 Neurocranial capsule cover consists of the
skin and the dura mater
 Orofacial capsule covers consist of the skin
and mucosa

 All spaces intervening between functional

components themselves, and between them
and the limits of the capsule, are filled with
indifferent loose connective tissue
 Each capsule surrounds and protects a
functional matrix:

 The neural mass which consists of the brain

plus leptomeninges and, most important,
cerebrospinal fluid

 The orofacial mass consists of the

oronasopharyngeal functioning spaces

The common factor in both cases is that

the capsular matrices exist as volumes
Neurocranial
capsule
 In the case of the neural skull, it is quite easy to visualize
the calvarial bones as lying within a neurocranial capsule.
 The composition of this capsule in the adult:
 the so-called "five layers" of the scalp,
 the bone itself
 the two-layer dura mater

Parenthetically, the calvarial bones consist of a number of

contiguous skeletal units:
 outer table
 inner table
 diploic space (and variably sinuses)

Each of these microskeletal units obviously has its specific

periosteal matrix; muscles and vessels being good
examples
 Neurocranium deals with volume of neural
mass

 Moss- “It makes little difference whether or

not this neural mass contains a "normal"
amount of brain tissue. It is the total neural
mass volume which is morphogenetically
significant”
 “The expansion of this enclosed and protected
capsular matrix volume is the primary event in
the expansion of the neurocranial capsule

 The response of the capsule, as a whole, is to

expand in a compensatory manner

 All of the included and enclosed functional

cranial components, i.e. the periosteal matrices
and their microskeletal units, are then
obligatorily carried outward within the capsule
in a totally passive manner”
 It is extremely important to note here that
such translations (calvarial functional cranial
components) occur without the necessity of
involving the processes of selective
periosteal apposition and resorption
 In the neurocranium, hydrocephaly is a condition
 The expansion of the neurocranial capsule is
always proportional to the increase in neural mass

 But this same increase in intracranial pressure

effectively obliterates vascular flow within the
capsule and so prevents periosteal accretion of
bone at sutural areas, thus producing the
characteristic excessively large fontanelles and
other sutural dehiscences

 Similarly inhibited is the growth of periosteal

matrices which normally produce the increasing
differentiation of the inner and outer tables and of
the diploic space.
 INFERENCE:
 The neural skull does not grow first
providing space for the secondary
expansion of the neural mass. Rather, the
expansion of the neural mass is the primary
event which causes the secondary and
compensatory growth of the neural skull
Orofacial matrices
 All functional cranial components of the
facial skull arise, grow, and are maintained
within an orofacial (splanchnocranial)
capsule.

 This capsule surrounds and protects the

oronasopharyngeal functioning spaces.

 It is the volumetric growth of these spaces

which is the primary morphogenetic event in
facial skull growth
 The functional reality of the respiratory and
digestive systems is their (oronaso-pharangeal
space) patency and the volume of that patency
is related to the general metabolic demands of
the body as a whole

 The oronasopharyngeal functioning space is

particularly related to the relatively dominant
cranial respiratory functional space volume
 The oral and pharyngeal "regions" are said to have a
primary function in maintaining a patent airway

 This is accomplished by a dynamic musculo-skeletal

postural balance which is termed the "airway-
maintenance mechanism“

 Bosma believes that "a recent concept is the

development of head and neck posture about this
pharyngeal airway" and that the related functional
cranial components are so dynamically balanced that
this airway is maintained throughout the range of
motion of the head and neck
 Postnatal development of the tongue is also
integrally related to the acquisition of an
open masticatory cavity

 It is the expansion of available performance

area which makes the anteriorward
elongation and greater motility of the tongue
feasible and possible
 Orofacial capsular matrix comes into being
in those embryonic stages during which the
several facial processes (medial and lateral
nasal, mandibular, and maxillary) arise

 Growth of the primordial capsule actually

forms the oronasal functioning space
 Originally, the presumptive oronasal space
is no more than a stomodeal membrane.

 Rupture of the stomodeal membrane joins

the endodermally enclosed pharyngeal
space to the common oronasal volume

 Formation of Oronasalpharangeal space

Orofacial capsular growth now is a

response to the volumetric increase of this
same space
Mandibular growth
 Demonstrates the integrated activity of periosteal
and capsular matrices in facial growth

 Mandibular condylar cartilages are not primary

sites of mandibular growth
 They are the loci at which secondary,
compensatory periosteal growth occurs

 Bilateral removal of mandibular condylar cartilages

in growing experimental animals, as in man, does
not inhibit:
 The spatial translation of the condylar complex
NEITHER
 It inhibits the changes in the form of their
microskeletal units
 The condylar skeletal unit ceases to exist,
and certain skeletally reflected
compensatory changes in other contiguous
mandibular cranial components occurs due
to the loss of lateral pterygoid activity
 If there are no condylar
processes does the "mandible"
(as a whole) alter its spatial
position?
 ANSWER: NO

 It is only by considering that the

orofacial capsule expands in response to
the morphogenetically prior volumetric
expansion of the orofacial functioning
spaces that we can comprehend the
observed translation in space
 Mandibular growth is seen to be a combination of the
morphologic effects of both capsular and periosteal matrices

 The capsular matrix growth causes an expansion of the capsule

as a whole

 The enclosed and embedded macroskeletal unit (the

"mandible" as a whole),is passively and secondarily translated
in space to successively new positions

 In normal conditions the periosteal matrices related to the

constituent mandibular microskeletal units also respond to this
volumetric expansion

 Such an alteration in their spatial position inevitably causes

them to grow; that is, causes changes in their functional
demands

 The sum of translation plus changes in form comprises the

totality of mandibular growth.
 Two points are implicit:

(1) If the periosteal matrices are not capable of functioning

normally, their specifically related skeletal units will alter
their spatial position (that is, be translated) without
undergoing consequent changes in their size and shape

(2) It is only when we conceptually combine the effects of

both capsular and periosteal matrices, of growth
changes in both position and form of the skeletal units,
that we begin to comprehend the phenomenon of facial
growth totally.
 Summary
 A brief review of the fundamental postulates of the method
of functional cranial analysis is given, with particular
emphasis on the definition of the functional matrix.

 Two basic types of such matrices— periosteal and

capsular

 Periosteal matrices include muscles and teeth

 The capsular matrices are conceived of as volumes

enclosed and protected by both the neurocranial and the
orofacial capsules

 In the neural skull the capsular matrix is the neural mass

 In the facial skull (Orofacial capsule) the matrix is the

functioning space of the oronasopharyngeal cavity.
 We noted the following differences between the activity of
periosteal and capsular functional matrices:
 Periosteal matrices act upon skeletal units in a direct
fashion by the processes of osseous deposition and
resorption (or of cartilaginous or fibrous tissue multiplication).
Their net effect is to alter the form (size and shape) of their
respective skeletal units

 Capsular matrices act upon functional cranial components

as a whole in a secondary and indirect manner. They do so
by altering the volume of the capsules within which the
functional cranial components are embedded

 The effect of such growth changes is to cause a passive

translation of these cranial components in space

 Cranial growth is a combination of the morphogenetically

primary activity of both types of matrix

 Growth is accomplished by both spatial translation and

changes in form
FUNCTIONAL MATRIX
REVISITED

By: Melvin Moss

1997- A.J.O (July-October)

 The periodic incorporation of
advances in the biomedical,
bioengineering, and computer
sciences allow the creation of
increasingly more comprehensive
revisions of the functional matrix
hypothesis
 FMH R 1- MECHANOTRANSDUCTION

 FMH R 2- OSSEOUS CONNECTED

CELLULAR NETWORK

 FMH R 3- THE GENOMIC THESIS

 FMH R 4- THE EPIGENETIC ANTITHESIS AND

RESOLVING SYNTHESIS
  The inclusion of the concepts and
databases that are related to the
intracellular and intercellular bone cell
mechanisms
+
processes of mechanotransduction & the
organization of bone as a biologic
connected cellular network
 permits revision of the functional matrix
hypothesis
 These translate the informational content of
a periosteal functional matrix stimulus into a
skeletal unit (bone) cell signal

 Donald Enlow “concept is evaluated in

the light of parallel biologic theory”
 The new version deals only with the responses from
periosteal matrices. It includes the molecular and cellular
processes underlying the triad of active skeletal growth
processes: deposition, resorption, and maintenance

 Histologic studies of actively adapting osseous tissues

demonstrate that:
 adjacent adaptational tissue surfaces simultaneously show
deposition, resorption, and maintenance

 adaptation is a tissue process. Deposition and

maintenance are functions of relatively large groups
(cohorts, compartments) of homologous osteoblasts, never
single cells

 a sharp demarcation exists between adjacent cohorts of

active, depository, and quiescent (resting) osteoblasts.
Why revisited FMH??
Constraints of the
FMH
 Initially, the FMH provided only qualitative
narrative descriptions of the biologic
dynamics of cephalic growth, at the gross
anatomic level, and it had two explanatory
constraints:

 Methodologic

 Hierarchical
 Methodologic constraint
Measurement techniques –
eg – roentgenographic cephalometry
Method specific – not structurally detailed

FEM – quantitative aspect of localized cephalic

growth kinematics
 Hierarchical constraint
Downwards –cellular, subcellular or
molecular

upwards – multicellular processes

“suspended” or “sandwiched” b/w two levels

 At present, no hypothesis provides a
comprehensive, coherent and integrated
description of all the processes and mechanisms
involved in bone growth, remodeling, adaptation,
and maintenance at all structural levels

 The FMH revisited version, presented herein,

transcends some hierarchical constraints and
permits seamless descriptions at, and between,
the several levels of bone structure and operation-
from the genomic to the organ level.
 It does so by the inclusion of two
complementary concepts:
 Mechanotransduction that occurs in single
bone cells

 Bone cells are computational elements that

function multicellularly as a connected
cellular network
 Anatomic and conceptual basis
 The developmental origin of all cranial skeletal
elements and all their subsequent changes in size,
shape and location, as well as their maintenance in
being, are always , without exception , secondary,
compensatory and mechanically obligatory responses
to the temporally and operationally prior demands of
their related cephalic non-skeletal cells, tissues,
organs and operational volumes.
Mechanotransduction
 All vital cells are "irritable" or perturbed by and
respond to alterations in their external
environment.
 Mechanosensing processes enable a cell to
sense and to respond to extrinsic loadings,by
using the processes of mechanoreception and of
mechanotransduction

 The former transmits an extracellular physical

stimulus into a receptor cell
 The latter transduces or transforms the stimulus's
energetic and/or informational content into an
intracellular signal
 MECHANOSENSATION

MECHANORECEPTION MECHANOTRANSDUCTION

INTRACELLULAR SIGNAL
 Mechanotransduction is one type of cellular
signal transduction.
 There are several mechanotransductive
processes, for example
 Mechanoelectrical
 Mechanochemical

 Whichever are used, bone adaptation

requires the subsequent intercellular
transmission of the transduced signals
 Osseous
Mechanotransduction
 Loadings are continuously applied to bone tissues,
tending to deform both extracellular matrix and
bone cells

 When an appropriate stimulus parameter exceeds

threshold values, the loaded tissue responds by
the triad of bone cell adaptation processes

 Both osteocytes and osteoblasts are competent

for intracellular stimulus reception and
transduction and for subsequent intercellular
signal transmission.
 LOADING

STATIC DYNAMIC

deformation

Extracellular matrix bone cells

threshold

Triad of bone cell adaptation

 Osteoblasts directly regulate bone deposition and
maintenance and indirectly regulate osteoclastic
resorption

 Osseous mechanotransduction is unique in four

ways:
1) Most other mechanosensory cells are cytologically
specialized, but bone cells are not

2) One bone-loading stimulus can evoke three adaptational

responses, whereas nonosseous processes generally
evoke one

3) Osseous signal transmission is aneural, whereas all

other mechanosensational signals use some afferent
neural pathways

4) The evoked bone adaptational responses are confined

within each "bone organ" independently, e.g., within a
femur, so there is no necessary "interbone" or organism
involvement
 There are two, possibly complementary,
skeletal cellular mechanotransductive
processes:

 Ionic
 Mechanical
Ionic or electrical processes
 This involves some processes of ionic transport
through the bone cell (osteocytic) plasma
membrane

 Stretch-activated channels-
 Plasma membrane stretch-activated (S-A) ion
channels

 Structure found in bone cells & in many other cell

types,significantly in fibroblasts

 When activated in strained osteocytes, they permit

passage of a certain sized ion or set of ions,
including K+, Ca2+ & Na+
 Such ionic flow may, in turn, initiate
intracellular electrical events, for example,
bone cell S-A channels may modulate
membrane potential as well as Ca2+ ion flux

 Osteocytic mechanoreceptor strain

sensitivity: Strain range- 1000 to 3000 µe
 Electrical processes include several
mechanotransductive processes:

 Electromechanical
 Electrokinetic
 Electric field strength
 Electrical processes

Electromechanical Electrokinetic Electric

field strength

Voltage activated Streaming potential Exogenous

ion channels electrical fields
Endogenous
Transmembrane electrical fields
ion flow (muscle activity)
Mechanical processes
 The mechanical properties of the extracellular
matrix influence cell behavior

 Loaded mineralized bone matrix tissue is

deformed or strained

 Recent data indicate that a series of extracellular

macromolecular mechanical levers exist, capable
of transmitting information from the strained matrix
to the bone cell nuclear membrane
 The bone cell molecule is connected
extracellularly with the macromolecular
collagen of the organic matrix and
intracellularly with the cytoskekeletal actin

 The molecules of the latter, in turn, are

connected to the nuclear membrane, at
which site the action of the mechanical lever
chain previously noted initiates a
subsequent series of intranuclear processes
regulatory of genomic activity.
 It is suggested that such a cytoskeletal
lever chain, connecting to the nuclear
membrane, can provide a physical
stimulus able to activate the osteocytic
genome

 It is by such an interconnected physical

chain of molecular levers that periosteal
functional matrix activity may regulate
the genomic activity of its strained
skeletal unit bone cells
SUMMARY
 Loading

Static Dynamic

Mechanosensing

Mechanoreception (Input)

Mechanotransduction

Ionic/Electrical Mechanical

S-A channels Electro Electro Field Macromolecular

mechanical kinetic strength

Skeletal unit cell

CCN Deposition
Resorption
Response (Output) Maintainence
FUNCTIONAL MATRIX REVISITED
- IInd SERIES
 Offers:
An explanatory chain, extending from the
epigenetic event of muscle contraction

hierarchically downward

to the regulation of the bone cell genome.

(Am J Orthod Dentofac Orthop 1997;112:221-6.)
 The first article in this series considered
the implications for the functional matrix
hypothesis (FMH); the ability of bone cells to
carry out intracellular mechanosensation
and transduction and intercellular
communication

 Second article: Inclusion of connectionist

network theory.
“BONE AS AN OSSEOUS CONNECTED
CELLULAR NETWORK (CCN)”
 OSSEOUS
CONNECTED
CELLULAR NETWORK
 All bone cells (except Osteoclasts) are interconnected by GAP
JUNCTIONS (Connexin-Major protein)

Forms OSSEOUS CONNECTED CELLULAR NETWORK (CCN)

 Each osteocyte is enclosed within its mineralized lacuna

 Gives off cytoplsmic processes (Canalicular processes);

n=+/- 80

 Around 15 mm long and arrayed three dimensionally

 Interconnected with processes of atleast 12 neighbouring cells

 Processes lie within mineralized bone matrix channels

(CANALICULI)
 Small spaces b/w cell process plasma membrane
and canalicular wall is filled with macromolecular
complexes

CCN (True syncytium)

 In Compact bone:
1) Canaliculi forms extensive communication b/w
osteons and Interstitial regions
2) Gap junctions form connection b/w:
Superficial osteocytes
&
Periosteal + Endosteal osteoblasts
(Connected laterally)
 Gap junctions connect:
Periosteal osteoblast

&
Pre-osteoblastic cells
(Vertically)
 Gap junctions permits:
1) Intercellular transmission of ions and small
molecules
2) Exhibits both electrical and fluorescent dye
transmission. Hence contributes to both Electrical
and Chemical synapses
3) Bidirectional signal traffic

 Bone cells:- Electrically active;

  Mechanotransducively activated bone cells
“OSTEOCYTES”

Initiate membrane action potential

Capable of transmission through gap junctions

Ionic signal Secondary messenger

* Mostly involved * Produced during bone
* Too rapid cell transduction
* Mechanosensory * Small biochemical
molecule
 CCN- “Artificial Neural Network”

 Intercellular signals created by an electrical type of

mechanotransduction of periosteal functional matrix
stimuli

Computationally processed in a multiprocessor network

mode

Computed network output informational signals move

hierarchally upward

Regulates the skeletal unit adaptational response of

osteoblast
  CCN (Connected Cellular Network) -

Connectionist theory Network theory

* Bone cells with many * Cells are organized
interconnections into layers:

Initial Input Final Output Intermediate/

Hidden layer

 Each cell in any layer- receives several

weighted inputs
“ STIMULI”
 Each cell of Initial input layer:
 Receives “LOADINGS” or weighted inputs

 Within each cell independently:

 All weighted inputs are summed

 Each cell is considered to have some minimal or

threshold value against which the sum of weighted
input is compared
 If the sum>threshold value

Intercellular signal generated

“MECHANOTRANSDUCTION”

Transmitted to all the intermediary/hidden layers

“ADJACENT OSTEOCYTES” connected via gap
junctions
  Similar processes of weighted signals undergo
summation; comparison; & transmission to

Final layer cell (OSTEOBLAST)

 Output of the final layer cell determines :

1) Site
2) Rate
3) Direction
4) Magnitude
5) Duration
of the specific adaptive response:-
i.e. 1) Deposition
2) Resorption
3) Maintainence
 CHARACTERISTICS OF CCN
 Information is not stored discretely in CCN

 Several types of information stored simultaneously

 CCN is redundant i.e. Error/Fault tolerant

 CCN shows oscillation i.e. Alternative reciprocal

signaling/Feedback b/w layers
Bidirectional flow of information through gap
junctions are the cytological basis for oscillatory
behavior of CCN

 Are not reducible i.e. neither apparent nor

predictable from a prior knowledge of the
attributes of individual cell
 Prevent flow of information
All the osteoblasts of a specific group
engaged in an identical adaptation process:
OPEN GAP JUNCTION
B/w groups of phenotypically different
osteoblasts:CLOSED GAP JUNCTION

 Informational network can also transmit

inhibitory signals
 Biologically:
Loading of bone cells occur in 3 dimensions

Gradient of deformation exists

(Each osteocyte has a uniquely different strain
property)

Hence,osteocyte potentially transmits three different

adaptational signals:

Stimulatory Inhibitory
 ROLE OF PERIOSTEAL
FUNCTIONAL MATRICES
 Morphogenetic primacy of periosteal functional
matrices on their skeletal units is consensually
accepted
As muscular demands alter
“Myectomy,Myotomy,Hypertrophy,
Augmentation,Repositioning”

Triad of active bone growth processes

Correspondingly adapts the form of its related

skeletal unit
 Extrinsic physical loading tends to deform
bone tissue and invoke skeletal unit (bone)
adaptation responsive processes

Stimulation via neural afferents to

muscles/tendons should be excluded

Classic example- Coronoid process forms by

temporalis muscle
 Periosteal osteoblasts may be directly
stimulated via mechanosensory processes

 Bone cells are competent mechanoreceptors

via there three dimensional array of
extensive canalicular cell processes to sense
deformation of mineralized matrix
 Strain is a competent stimulus

 May vary with specific conditions:

 Localized category- Bone responds better to
dynamic rather than static loading

 Frequency- Osteocytes are physiologically tuned to

the frequency of muscle function

 Magnitude- Strain magnitude of 2000

+/-1000 microstrain (me) is competent

Frequencies related to bone adaptational

response are present within the muscle contraction
“Bone is "tuned" to the precise
frequencies of skeletal muscle
activity”
 CONCLUSION
 The original FMH version offered only :
 Verbal descriptions of periosteal matrix function
and skeletal unit response

 Addition to the FMH of the concepts of

mechanotransduction and of computational
bone biology
Offers an explanatory chain:-
Extending from the epigenetic event of skeletal
muscle contraction

Hierarchically downward

Through the cellular and molecular levels to the

bone cell genome

And then upward again

Through histologic levels

To the event of gross bone form adaptational

changes.
FUNCTIONAL MATRIX

HYPOTHESIS

REVISITED-

III & IV series

rd th
 Initial versions of the functional matrix hypothesis
(FMH) theoretically posited the ontogenetic
primacy of “function”

 Dominant scientific paradigm suggested that

genomic, instead of epigenetic (functional) factors,
regulated (cause, control) growth

HENCE

An analysis of this continuing controversy was

deemed useful
BASIS FOR GENOMIC

HYPOTHESIS

( Classical chromosomal
Mendelian genetics )
 “The whole plan of growth, the whole series of
operations to be carried out, the order and site of
synthesis and their co-ordination are all written
down in the nucleic acid message”

 “Within the fertilized egg lies the information

necessary to generate a diversity of cell types in
the precise pattern of tissues and organs that
comprises the vertebrate body”
 GENOMIC

v/s

EPIGENETIC

CONTROVERSY
 Epigenetic / Genomic problem is a Dichotomy

 Dialectics is one analytical method for its

resolution

 Method consists of the presentation of two

opposing views:
 Thesis and an Antithesis
&
 Resolving synthesis
 Odontogenic
example
of the
Genomic/Epigenetic
Dichotomy
 GENOMIC SUPPORT
 Rigid genomic control of odontogenesis

 Expression of the genomically regulated

production of specific molecules as
exhibited, in murine molar development
 EPIGENETIC SUPPORT
 Eg.- Chiclid fish are polyphyodont (have
continuously replacing dental sets) and can exhibit
pronounced dental phenotypic plasticity

 When the fish are fed on hard-shelled mollusks,

the replacing teeth are large and molariform

 When soft food is fed, those teeth are gracile,

conical, and non-molariform

Altered dental generations by alternating diet's

consistency
THE GENOMIC

THESIS
 Holds that the genome, from the moment of
fertilization, contains all the information necessary
to regulate (cause, control, direct):

 The intra-nuclear formation and transcription of

mRNA

 Regulate all the intracellular and intercellular

processes of subsequent, and structurally more
complex, cell, tissue, organ, and organismal
morphogenesis

“All features are ultimately determined by the

DNA sequence of the genome”
 “Morphogenesis is but the predetermined reading-
out of an intrinsic and inherited genomic
organismal blueprint”

 Genome also regulates the geometric attributes of

cell, tissue, organ, and organismal size, shape,
and location

 Mechanisms by which a fertilized egg divides and

progresses through the various decision points to
yield groups of cells that are first determined to
become and then actually differentiate to become
specialized tissues of the right dimension and in
the proper location
 Mega-human genome project, called
“The ultimate triumph of genetics” intends to:

 Describe the complete human genome

 Demonstrate genomic controls of all developmental

processes, at all structural levels, from the sub-
cellular to the organismal

 Lead to some type of Neoeugenics

 Human activities now are claimed to be
genomically regulated:-

 e.g.,psychological behavior
personality
alcohol and drug abuse
chronobiological cyclic behaviors
smoking
obesity
alcoholism
drug abuse
food-binging—indeed any attention-deficiency
disorder
Biologic Bases

for the

Genomic Thesis
 Somatic cells of an individual inherit two
classes of molecular information:

 An identical diploid DNA

 The maternal cytoplasmic constituents of

the egg: e.g., mitochondria, cytoskeleton,
membranes
 10% of the genome seems related to phenotypic
ontogenesis

 90% does not encode precursors to mRNA’s or

any other RNA

 All somatic cells commonly share approximately

5000 different polypeptide chains

 Each specific cell type is characterized only by

approximately 100 specific proteins

It is claimed that “these quantitative (protein)

differences are related to differences in cell size,
shape and internal architecture”
 10% of the DNA exists in two families:

“Housekeeping” genes Nonabundant “Structural" genes

 HOUSEKEEPING GENES
 Regulate the normal molecular synthesis of agents
involved in
 The common energetic (metabolic, respiratory)
activities of all cells
 The specific activities of special cell types (e.g.,
neurons, osteoblasts, ameloblasts etc )

 Also regulate the synthesis of the specific

molecular gene products, whose presence,
absence, or abnormal molecular configuration are
associated with the (human) pathologic conditions
said to have a unitary genetic cause—the so-
called Mendelian disorders and the single-gene
disorders with nonclassic inheritance, such as
Marfan syndrome,
The Genomic Thesis

in

Orofacial Biology
Craniofacial development is controlled by two
interrelated, processes:

Regulatory (homeobox) gene activity Subsequent activity of

two regulatory molecular
groups:

Growth factor families Steroid/thyroid/retinoic acid super-family

 Homeobox genes:

 coordinate the development of complex

craniofacial structures

 regulation of the development of virtually all of the

skeletal and connective tissue of the face

 Regulatory molecules:

 alter the manner in which homeobox genes

coordinate cell migration and subsequent cell
interactions that regulate growth

 involved in the “genetic variations” causing, or

contributing to, the abnormal development of
relatively common craniofacial malformations
 Orthodontic

implications

of the

Genomic thesis
 Defect in the regulatory activity of genes or gene
expression governing the size of the teeth and
jaws

Malocclusion and dentofacial deformities

 CRITICAL

DEFINITIONS
 To solve dichotomy…
 Epigenetics

 Hierarchy

 Emergence

 Causation
 Epigenetics….
 All the extrinsic factors impinging on the vital
structures – mechanical loadings / electrical
signals

 All intrinsic events occuring in the cell and

between the cell
 Hierarchy…..
 Levels of organization

 Sub atomic atom molecule subcellular

organism organ tissue cell

 Genomic thesis
 Epigenetic antithesis
 Emergence…..
 Appearance of attributes at each successive
higher level

 Changes in attributes – cannot be predicted

Osteocytes and bone tissue

Emergence is not genomically controlled

 Causation….
 How the attributes of a given biologic
structural level cause (control, regulate and
determine) the attributes of next higher level

Genomic thesis
Epigenetic antithesis
Coronoid and temporalis
 Classification of causation…..
 Material (what is acted upon?)
Intrinsic ;prior causes
 Formal (by what rules?)

 Efficient (what was the immediate preceding event?)

Extrinsic ;
proximate

 Final (why?)
CONCLUSION :
 Morphogenesis is regulated by both genomic and
epigenetic processes, mechanisms

 Both are necessary causes, neither alone are

sufficient causes.

 Their integrated activities provide the necessary and

sufficient causes for growth and development
 A

RESOLVING

SYNTHESIS
“It seemed that the next minute they would
discover a solution. Yet it was clear to both
of them that the end was still far, far off,
and that the hardest and most complicated
part was only just beginning”
–Anton Chekov
 Morphogenesis is regulated (controlled, caused)
by the activity of both:

Genomic Epigenetic processes

 Both are necessary causes; neither alone are

sufficient causes;

And

 Only their integrated activities provides the

necessary and sufficient causes of growth and
development
 Genomic factors are considered as intrinsic
and prior causes

 Epigenetic factors are considered as

extrinsic and proximate causes
Materials Formal Efficient Final
Cellular/ Genomic code Epigentic factors
intercellular “laws”
materials

Sufficient

Morphogenesis