Functional matrix hypothesis revisited

Morphogenesis – the evolution andMorphogenesis – the evolution and
development of form, as the developmentdevelopment of form, as the development
of the shape of a particular organism orof the shape of a particular organism or
part of the body or the developmentpart of the body or the development
undergone by the individuals who attainundergone by the individuals who attain
the type to which the majority of thethe type to which the majority of the
individuals of the species approximate.individuals of the species approximate.
Temporal – Pertaining to time; limited asTemporal – Pertaining to time; limited as
to time.to time.
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 The developmental origin of all cranialThe developmental origin of all cranial
skeletal elements (e.g. skeletal units) & allskeletal elements (e.g. skeletal units) & all
their subsequent changes in size andtheir subsequent changes in size and
shape (e.g. form) and location, as well asshape (e.g. form) and location, as well as
their maintenance in being, are always,their maintenance in being, are always,
without exception, secondary,without exception, secondary,
compensatory, and mechanicallycompensatory, and mechanically
obligatory responses to the temporally andobligatory responses to the temporally and
operationally prior demands of theiroperationally prior demands of their
related cephalic non skeletal cells, tissues,related cephalic non skeletal cells, tissues,
organs, and operational volumes (e.g. theorgans, and operational volumes (e.g. the
functional matrices).functional matrices).

The Periosteal MatricesThe Periosteal Matrices
PeriosteumPeriosteum
 Outer fibrous membrane (limiting membrane)Outer fibrous membrane (limiting membrane)
 Inner cellular layer (osteogenetic layer)Inner cellular layer (osteogenetic layer)
Functions of PeriosteumFunctions of Periosteum
 Medium for attachment.Medium for attachment.
 Nutritive function (blood vessels).Nutritive function (blood vessels).
 Osteogenetic function.Osteogenetic function.
 Limiting fibrous membrane.Limiting fibrous membrane.

Periosteal MatrixPeriosteal Matrix
Cranial Capsule
Functional cranial component
Functional Matrix Skeletal Unit
Macro Skeletal
e.g. coronoid
Micro Skeletal
e.g. calvaria
Periosteal Matrix
e.g. temporalis muscle
Capsular Matrix
e.g. orofacial capsule

Periosteal functional matrix affectsPeriosteal functional matrix affects
deposition and resorption of adjacent bonydeposition and resorption of adjacent bony
tissues, therefore the matrix controlstissues, therefore the matrix controls
remodeling and the size and shape of aremodeling and the size and shape of a
bone.bone.
e.g. the interaction between the temporalise.g. the interaction between the temporalis
muscle and the coronoid process of themuscle and the coronoid process of the
mandible.mandible.

 Muscles are one excellent example of periostealMuscles are one excellent example of periosteal
functional matrices. Other components are –functional matrices. Other components are –
blood vessels, nerves and glands that producesblood vessels, nerves and glands that produces
morphologic changes in their related skeletalmorphologic changes in their related skeletal
units in a completely homologous manner.units in a completely homologous manner.
 The associated skeletal unit plays the necessaryThe associated skeletal unit plays the necessary
biomechanical role of providing protection andbiomechanical role of providing protection and
support to this functional matrix which actuallysupport to this functional matrix which actually
carries out the function.carries out the function.

Functional Matrix Hypothesis-Functional Matrix Hypothesis-
RevisitedRevisited
 Need of FMH revisited.Need of FMH revisited.
 FMH initially provided description at grossFMH initially provided description at gross
anatomic level.anatomic level.
 Constraints of previous version.Constraints of previous version.
 Controversy concerning the roles ofControversy concerning the roles of
genomic and nongenomic (epigenetic)genomic and nongenomic (epigenetic)
processes in the regulation (causation) ofprocesses in the regulation (causation) of
growth.growth.

RevisitedRevisited
 the combination of genomic andthe combination of genomic and
epigenetic factors is a necessary cause ofepigenetic factors is a necessary cause of
craniofacial growth.craniofacial growth.
 Therapeutic intervention is always anTherapeutic intervention is always an
epigenetic event.epigenetic event.
 Moss stressed on epigenetic primacy.Moss stressed on epigenetic primacy.

 Few clinicians might agree that "theFew clinicians might agree that "the
morphology of all of the bones of themorphology of all of the bones of the
craniofacial complex is under the rathercraniofacial complex is under the rather
rigid control of hereditary forces.“rigid control of hereditary forces.“
 Krogman stated that, in craniofacialKrogman stated that, in craniofacial
genetics, we deal with growth changesgenetics, we deal with growth changes
that are the result of the interplay of genesthat are the result of the interplay of genes
plus the environment.plus the environment.
RevisitedRevisited

Points against genomic hypothesisPoints against genomic hypothesis
 The relationship between genotype andThe relationship between genotype and
phenotype of man and the great apes.phenotype of man and the great apes.
 Polypeptides (a product of genomicPolypeptides (a product of genomic
activity) of man and chimpanzee are 99activity) of man and chimpanzee are 99
percent identical, while the two speciespercent identical, while the two species
display great anatomic and physiologicdisplay great anatomic and physiologic
differences.differences.

Points against genomic hypothesisPoints against genomic hypothesis
 Sibling species of Drosophila, and of certainSibling species of Drosophila, and of certain
mammals, show little observable phenotypicmammals, show little observable phenotypic
difference and great genomic difference.difference and great genomic difference.
 Many groups of closely related species do notMany groups of closely related species do not
differ much in form, behavior, and even generaldiffer much in form, behavior, and even general
genetic constitution but display outstandinggenetic constitution but display outstanding
differences in the number and form ofdifferences in the number and form of
chromosomes. In horses the number ofchromosomes. In horses the number of
chromosomes ranges between 32 and 62.chromosomes ranges between 32 and 62.

The epigenetic hypothesisThe epigenetic hypothesis
 Epigenetics involves the production of newEpigenetics involves the production of new
information during development asinformation during development as
structure and function becamestructure and function became
increasingly complex.increasingly complex.
 These alterations of state (that is, newThese alterations of state (that is, new
information) act significantly to regulateinformation) act significantly to regulate
subsequent developmental stages, as wellsubsequent developmental stages, as well
as to regulate genomic reaction to theseas to regulate genomic reaction to these
altered environmental states.altered environmental states.

 In this hypothesis, "environment" is not justIn this hypothesis, "environment" is not just
permissive and supportive but also regulative.permissive and supportive but also regulative.
 The functional matrix hypothesis hasThe functional matrix hypothesis has
demonstrated repeatedly that the presence, anddemonstrated repeatedly that the presence, and
growth changes in size, shape, and location, ofgrowth changes in size, shape, and location, of
all craniofacial skeletal attributes areall craniofacial skeletal attributes are
epigenetically regulated (e.g. mandibularepigenetically regulated (e.g. mandibular
coronoid process).coronoid process).

 Neurotrophic regulation of the muscle cellNeurotrophic regulation of the muscle cell
genome - following motor denervation,genome - following motor denervation,
marked changes in many of the RNAmarked changes in many of the RNA
sequences present in the muscle cellssequences present in the muscle cells
were noted.were noted.
 Cleft lip and palate in man, probablyCleft lip and palate in man, probably
reflect epigenetic factors rather thanreflect epigenetic factors rather than
cytoplasmic inheritance.cytoplasmic inheritance.

The epigenetic landscapeThe epigenetic landscape

Constraints of FMHConstraints of FMH
 According to Moss, FMH provided onlyAccording to Moss, FMH provided only
qualitative narrative descriptions ofqualitative narrative descriptions of
cephalic growth, at the gross anatomiccephalic growth, at the gross anatomic
level.level.
 These constraints are grouped asThese constraints are grouped as
1. Methodologic constraint.1. Methodologic constraint.
2. Hierarchical constraint.2. Hierarchical constraint.

Methodologic ConstraintMethodologic Constraint
 Macroscopic measurements, use theMacroscopic measurements, use the
technique of point mechanics and arbitrarytechnique of point mechanics and arbitrary
reference frames (e.g. roentgenographicreference frames (e.g. roentgenographic
cephalometry) permitted only methodcephalometry) permitted only method
specific descriptions that cannot bespecific descriptions that cannot be
structurally detailed.structurally detailed.

Methodologic ConstraintMethodologic Constraint
 This constraint was removed by theThis constraint was removed by the
continuum mechanics techniques of thecontinuum mechanics techniques of the
finite element method (FEM) which addedfinite element method (FEM) which added
descriptions of quantitative aspects ofdescriptions of quantitative aspects of
localized cephalic growth to earlierlocalized cephalic growth to earlier
qualitative descriptions of growth.qualitative descriptions of growth.

Hierarchical ConstraintHierarchical Constraint
 Hierarchy – The ordering or classificationHierarchy – The ordering or classification
of anything in ascending or descendingof anything in ascending or descending
order of importance.order of importance.
 Previous version’s descriptions did notPrevious version’s descriptions did not
extend “downwards” to process at theextend “downwards” to process at the
cellular, sub cellular or molecularcellular, sub cellular or molecular
structural domains or extends “upwards”structural domains or extends “upwards”
to the multi cellular processes by whichto the multi cellular processes by which
bone tissues respond to lower levelbone tissues respond to lower level
signals.signals.

Hierarchical constraintHierarchical constraint
FMH could not describeFMH could not describe
1.1. How extrinsic epigenetic FunctionalHow extrinsic epigenetic Functional
Matrix stimuli are transduced intoMatrix stimuli are transduced into
regulatory signals by individual boneregulatory signals by individual bone
cells.cells.
2.2. How individual cells communicate toHow individual cells communicate to
produce coordinated multi cellularproduce coordinated multi cellular
responses.responses.

 Disjunctions in hierarchical theory.Disjunctions in hierarchical theory.
 In hierarchical theory attributes/features ofIn hierarchical theory attributes/features of
successively higher levels are not simplysuccessively higher levels are not simply
the sum of lower level attributesthe sum of lower level attributes

 Some Hierarchical constraints are overcome inSome Hierarchical constraints are overcome in
new FMH version, giving seamlessnew FMH version, giving seamless
descriptions between the several levels ofdescriptions between the several levels of
bone structure and operation from the genomicbone structure and operation from the genomic
to organ level.to organ level.
 This is done by including two concepts:This is done by including two concepts:
1.1. Mechanotransduction (occurs in single boneMechanotransduction (occurs in single bone
cells).cells).
2.2. That bone cells are computational elementsThat bone cells are computational elements
that function multicellularly as a connectedthat function multicellularly as a connected
cellular network.cellular network.

RevisitedRevisited
 Comprehensive revision of FMH. ItComprehensive revision of FMH. It
includes 2 topics:includes 2 topics:
1.Mechanisms of cellular1.Mechanisms of cellular
mechanotransduction.mechanotransduction.
2.Biologic cellular network theory.2.Biologic cellular network theory.

Functional MatrixFunctional Matrix
Hypothesis-RevisitedHypothesis-Revisited
Mechanotransduction — a cell's conversionMechanotransduction — a cell's conversion
of a mechanical stimulus into an electricalof a mechanical stimulus into an electrical
signal.signal.
Mechano – meaning mechanical or relatingMechano – meaning mechanical or relating
to motions of material bodiesto motions of material bodies
Transduction – the transforming of oneTransduction – the transforming of one
form of energy into another such as by theform of energy into another such as by the
sensory mechanisms of the body.sensory mechanisms of the body.

FMH-RevisitedFMH-Revisited
 This new version deals only with theThis new version deals only with the
responses to periosteal matrices.responses to periosteal matrices.
 It includes molecular and cellularIt includes molecular and cellular
processes underlying the triad of activeprocesses underlying the triad of active
skeletal growth processes – deposition,skeletal growth processes – deposition,
resorption and maintenance.resorption and maintenance.

FMH-RevisitedFMH-Revisited
 Histologic studies of actively adapting osseousHistologic studies of actively adapting osseous
tissues show:tissues show:
1. Adjacent adaptational tissue surfaces1. Adjacent adaptational tissue surfaces
simultaneously show deposition, resorption andsimultaneously show deposition, resorption and
maintenance.maintenance.
2. Deposition and maintenance are functions of2. Deposition and maintenance are functions of
relatively large groups (cohorts) of homologousrelatively large groups (cohorts) of homologous
osteoblasts, never single cells.osteoblasts, never single cells.
3. A sharp demarcation between cohorts of active3. A sharp demarcation between cohorts of active
and resting osteoblasts.and resting osteoblasts.

MechanotransductionMechanotransduction
 Process by which a cellProcess by which a cell
transduces/transforms the stimulus’stransduces/transforms the stimulus’s
energetic and informational content intoenergetic and informational content into
an intracellular signal.an intracellular signal.
 Mechanoreception – Is the transmission ofMechanoreception – Is the transmission of
an extracellular physical stimulus into aan extracellular physical stimulus into a
receptor cell.receptor cell.

 All vital cells are irritable and respond toAll vital cells are irritable and respond to
alterations in their external environment.alterations in their external environment.
 By various mechanosensory processes aBy various mechanosensory processes a
cell senses and responds to extrinsiccell senses and responds to extrinsic
loadings. This includes processes ofloadings. This includes processes of
mechanoreception andmechanoreception and

Mechanotransductive processesMechanotransductive processes
 Mechanoelectrical and Mechanochemical.Mechanoelectrical and Mechanochemical.
 Whichever are used bone adaptationWhichever are used bone adaptation
requires the subsequent intercellularrequires the subsequent intercellular
transmission of the transduced signals.transmission of the transduced signals.

Osseous MechanotransductionOsseous Mechanotransduction
 Static and dynamic loadings.Static and dynamic loadings.
 Deformation of extracellular matrix andDeformation of extracellular matrix and
bone cells.bone cells.
 Threshold value.Threshold value.
 Tissue response by triad of bones andTissue response by triad of bones and
adaptation processes.adaptation processes.

Osseous MechanotransductionOsseous Mechanotransduction
 Intracellular stimulus reception andIntracellular stimulus reception and
transduction by osteoblasts andtransduction by osteoblasts and
osteocytes.osteocytes.
 Intercellular signal transmission.Intercellular signal transmission.
 Osteoblasts directly regulate boneOsteoblasts directly regulate bone
deposition and maintenance and indirectlydeposition and maintenance and indirectly
regulate osteoclastic resorption.regulate osteoclastic resorption.

Features of OsseousFeatures of Osseous
1.1. Bone cells are not cytologicallyBone cells are not cytologically
specialized.specialized.
2.2. One bone loading stimulus evokes threeOne bone loading stimulus evokes three
adaptational responses.adaptational responses.
3.3. Osseous signal transmission is aneuralOsseous signal transmission is aneural
(no afferent neural pathway involved).(no afferent neural pathway involved).
4.4. Response confined within bone organResponse confined within bone organ
independently.independently.

Gap JunctionsGap Junctions
 Tight junctionTight junction
1. Macula adherens1. Macula adherens
2. Zonula adherens2. Zonula adherens
3. Zonula fasciculus3. Zonula fasciculus
 Gap junctionGap junction

Gap JunctionGap Junction
 Beads like structure between cell membraneBeads like structure between cell membrane
through which canaliculi passes.through which canaliculi passes.
 Permits intercellular transmission of ions andPermits intercellular transmission of ions and
small molecules.small molecules.
 Exhibits both electrical and fluorescent dyeExhibits both electrical and fluorescent dye
transmission.transmission.
 They are electrical synapses (contrary toThey are electrical synapses (contrary to
interneuronal chemical synapses).interneuronal chemical synapses).
 Permit bidirectional signal traffic e.g.Permit bidirectional signal traffic e.g.
biochemical, ionic.biochemical, ionic.

Skeletal CellularSkeletal Cellular
Mechanotransductive ProcessesMechanotransductive Processes
 Ionic or electrical processes.Ionic or electrical processes.
 MechanicalMechanical

Ionic ProcessIonic Process
 Ionic transport.Ionic transport.
 Intercellular transmission of ionic signal isIntercellular transmission of ionic signal is
computed by operation of osseouscomputed by operation of osseous
connected cellular network (CCN).connected cellular network (CCN).
 Network’s output regulates multicellularNetwork’s output regulates multicellular
bone responses.bone responses.
 Stretch activated channels.Stretch activated channels.

Electrical ProcessesElectrical Processes
 Involves plasma membrane andInvolves plasma membrane and
extracellular fluid. Electrical Processesextracellular fluid. Electrical Processes
are –are –
1.1. Electromechanical.Electromechanical.
2.2. Electrokinetic.Electrokinetic.
3.3. Electric field strength.Electric field strength.

Mechanical ProcessesMechanical Processes
 Alternative means of regulating bone cellAlternative means of regulating bone cell
genomic function.genomic function.
 Extracellular macromolecular mechanicalExtracellular macromolecular mechanical
levers.levers.
 Transmembrane molecule integrin.Transmembrane molecule integrin.
 Cytoskeletal actin.Cytoskeletal actin.

Mechanical ProcessesMechanical Processes
 Cytoskeletal lever chain connects toCytoskeletal lever chain connects to
nuclear membrane.nuclear membrane.
 Provides a physical stimulus fromProvides a physical stimulus from
functional matrix.functional matrix.
 Activates the osteocytic genome (cfosActivates the osteocytic genome (cfos
genes).genes).

Osseous connected cellularOsseous connected cellular
network (CCN)network (CCN)
 Connectionist network theoryConnectionist network theory
 Bone as an osseous CCNBone as an osseous CCN

CCNCCN
 Intercellular gap junctions permit bone cells toIntercellular gap junctions permit bone cells to
intercellularly transmit , and subsequentlyintercellularly transmit , and subsequently
process, periosteal functional matrix information,process, periosteal functional matrix information,
after its initial intracellular mechanotransduction.after its initial intracellular mechanotransduction.
 Gap junctions underlie the organization of boneGap junctions underlie the organization of bone
tissue as a connected cellular network, and thetissue as a connected cellular network, and the
fact that all bone adaptation processes arefact that all bone adaptation processes are
multicellular.multicellular.
 All bone cells are extensively interconnected byAll bone cells are extensively interconnected by
gap junctions forming osseous CCN (exceptgap junctions forming osseous CCN (except
osteoclasts).osteoclasts).

CCN structureCCN structure
 Connexin 43 is the major protein.Connexin 43 is the major protein.
 Each osteocyte has ~80Each osteocyte has ~80
cytoplasmic/canalicular processescytoplasmic/canalicular processes
(~15(~15µm).µm).
 Interconnect with similar processes of upInterconnect with similar processes of up
to 12 neighboring cells.to 12 neighboring cells.

 Processes lie within canaliculi (mineralizedProcesses lie within canaliculi (mineralized
bone matrix).bone matrix).
 Small space between cell process plasmaSmall space between cell process plasma
membrane and the canalicular wall is filledmembrane and the canalicular wall is filled
with macromolecular complexes.with macromolecular complexes.
 Gap junctions connect osteocytes toGap junctions connect osteocytes to
periosteal and endosteal osteoblasts.periosteal and endosteal osteoblasts.
 Osteoblasts are similarly interconnectedOsteoblasts are similarly interconnected
laterally.laterally.

 Vertically, gap junctions connectVertically, gap junctions connect
periosteal osteoblasts with preosteoblasticperiosteal osteoblasts with preosteoblastic
cells which in turn are similarlycells which in turn are similarly
interconnected.interconnected.
 CCN is a true syncytium.CCN is a true syncytium.
 Bone tissue in a very real sense is “hardBone tissue in a very real sense is “hard
wired”.wired”.

CCNCCN
 Mechanotransductively activated boneMechanotransductively activated bone
cells can initiate membrane Actioncells can initiate membrane Action
potential capable of transmission throughpotential capable of transmission through
interconnecting gap junctions.interconnecting gap junctions.
 Primacy of ionic signals over secondaryPrimacy of ionic signals over secondary
messengers.messengers.
 Time course of mechanosensoryTime course of mechanosensory
processes is too rapid to involveprocesses is too rapid to involve
secondary messengers.secondary messengers.

CCNCCN
 Parallel distributed signal processing.Parallel distributed signal processing.
 Intercellular signals processedIntercellular signals processed
computationally (as network).computationally (as network).
 Computed network output informationalComputed network output informational
signals move hierarchically “upward” tosignals move hierarchically “upward” to
regulate the skeletal unit adaptationalregulate the skeletal unit adaptational
responses of the osteoblasts.responses of the osteoblasts.

Network TheoryNetwork Theory
 Cells are organized into “layers”.Cells are organized into “layers”.
 An initial input, a final output, and one orAn initial input, a final output, and one or
more intermediate “hidden layers”.more intermediate “hidden layers”.
 The operational processes are identicalThe operational processes are identical
for all bone cells in all layers.for all bone cells in all layers.
 Each cell in any layer may simultaneouslyEach cell in any layer may simultaneously
receive several weighted inputs.receive several weighted inputs.

 In initial layer these inputs represent theIn initial layer these inputs represent the
loadings.loadings.
 Within each cell independently, all theWithin each cell independently, all the
weighted inputs are then summed.weighted inputs are then summed.
 This sum is then compared within the cellThis sum is then compared within the cell
against threshold value.against threshold value.
 If this value is exceeded, an intracellularIf this value is exceeded, an intracellular
signal is generated i.e. successfulsignal is generated i.e. successful

 This signal is then transmitted identically to allThis signal is then transmitted identically to all
hidden layer cells (adjacent osetocytes).hidden layer cells (adjacent osetocytes).
 Similar process of weighted signal summation,Similar process of weighted signal summation,
comparison and transmission occur incomparison and transmission occur in
intermediate layers until final layer cellsintermediate layers until final layer cells
(osteoblasts) are reached.(osteoblasts) are reached.
 The outputs of these anatomically superficialThe outputs of these anatomically superficial
cells determines the site, rate, direction,cells determines the site, rate, direction,
magnitude and duration of the specific adaptivemagnitude and duration of the specific adaptive
response i.e. triad of each cohort of osteoblasts.response i.e. triad of each cohort of osteoblasts.

Working of CCNWorking of CCN
 Information is not stored discretely inInformation is not stored discretely in
CCN.CCN.
 It is rather distributed across all/part ofIt is rather distributed across all/part of
network and several types of informationnetwork and several types of information
may be stored simultaneously.may be stored simultaneously.
 No informational representation of CCN,No informational representation of CCN,
thus network is error tolerant, i.e. , one orthus network is error tolerant, i.e. , one or
several inoperative cells cause little or noseveral inoperative cells cause little or no
noticeable loss in network operations.noticeable loss in network operations.

 CCNs show oscillations i.e. reciprocalCCNs show oscillations i.e. reciprocal
signaling (feedback) between layers.signaling (feedback) between layers.
 Gap junctions, permitting bidirectional flowGap junctions, permitting bidirectional flow
of information, are the cytological basis forof information, are the cytological basis for
the oscillatory behavior of a CCN.the oscillatory behavior of a CCN.
 All the osteoblasts of a cohort engaged inAll the osteoblasts of a cohort engaged in
an identical adaptation process arean identical adaptation process are
interconnected by open gap junctions.interconnected by open gap junctions.

 This attribute enables them to selfThis attribute enables them to self
organize.organize.
 Biologic CCNs are not preprogrammed.Biologic CCNs are not preprogrammed.
 They learn by unsupervised or epigeneticThey learn by unsupervised or epigenetic
training (probably by conformationaltraining (probably by conformational
changes in cytoskeleton).changes in cytoskeleton).
 These network attributes are notThese network attributes are not
predictable from a prior knowledge of thepredictable from a prior knowledge of the
attributes of individual cells.attributes of individual cells.

 The presence of sharp histologicalThe presence of sharp histological
discontinuities between cohorts ofdiscontinuities between cohorts of
phenotypically different osteoblasts isphenotypically different osteoblasts is
related to their ability to close gaprelated to their ability to close gap
junctions at the boundaries between suchjunctions at the boundaries between such
cohorts preventing flow of information.cohorts preventing flow of information.
 Informational networks also can transmitInformational networks also can transmit
inhibitory signals.inhibitory signals.

AssumptionsAssumptions
 It is assumed that bone cells areIt is assumed that bone cells are
organized in only two dimensions.organized in only two dimensions.
 Bone loading occur only at discrete loci.Bone loading occur only at discrete loci.
 Gradients of strain are not considered.Gradients of strain are not considered.

Biologic RealityBiologic Reality
 In a loaded 3-dimensional bone volumeIn a loaded 3-dimensional bone volume
gradients of deformation must exist.gradients of deformation must exist.
 Each osteocyte probably senses uniquelyEach osteocyte probably senses uniquely
different strain properties.different strain properties.
 Probably each osteocyte is able toProbably each osteocyte is able to
transmit three different adaptationaltransmit three different adaptational
signals in three different directions – somesignals in three different directions – some
stimulatory and some inhibitory.stimulatory and some inhibitory.

 The morphogenetic primacy of periostealThe morphogenetic primacy of periosteal
functional matrices on their skeletal unitsfunctional matrices on their skeletal units
is generally accepted.is generally accepted.
 As a muscular demand altersAs a muscular demand alters
(neurectomy, exercise, hypertrophy,(neurectomy, exercise, hypertrophy,
hyperplasia, atrophy, augmentation orhyperplasia, atrophy, augmentation or
repositioning), the triad of active bonerepositioning), the triad of active bone
growth processes correspondingly adaptsgrowth processes correspondingly adapts
the form of its specifically related skeletalthe form of its specifically related skeletal
unit.unit.

 Some periosteal osteoblasts may beSome periosteal osteoblasts may be
directly stimulated, but extant datadirectly stimulated, but extant data
suggested osteocytic primacy insuggested osteocytic primacy in
mechanosensory processes.mechanosensory processes.
 Their 3-dimensional array of extensiveTheir 3-dimensional array of extensive
canalicular cell processes is architecturallycanalicular cell processes is architecturally
well suited to sense deformation of thewell suited to sense deformation of the
mineralized matrix.mineralized matrix.

Strain AttributesStrain Attributes
 Significant strain attribute includesSignificant strain attribute includes
1. Loading category – Bone responds best to1. Loading category – Bone responds best to
dynamic than static loading.dynamic than static loading.
2. Frequency – Osetocytes may be physiologically2. Frequency – Osetocytes may be physiologically
“tuned” to the frequencies of muscle function.“tuned” to the frequencies of muscle function.
 Strain is a competent stimulus and probablyStrain is a competent stimulus and probably
plays primary role in bone adaptationalplays primary role in bone adaptational
responses.responses.
3. Magnitude – Relatively small microstrains3. Magnitude – Relatively small microstrains
(~10(~10 -6-6
mm/mm), and strain magnitudes of 2000mm/mm), and strain magnitudes of 2000 ±±
1000 µ, are morphogenetically competent.1000 µ, are morphogenetically competent.

 Skeletal muscle contraction is a typicalSkeletal muscle contraction is a typical
periosteal functional matrix loading event.periosteal functional matrix loading event.
 Fundamental frequency of contracting muscle isFundamental frequency of contracting muscle is
about 2Hz, other strain related harmonics of 15-about 2Hz, other strain related harmonics of 15-
40Hz exist.40Hz exist.
 Of particular significance to FMH is the closeOf particular significance to FMH is the close
similarity of muscle stimulus frequencies to bonesimilarity of muscle stimulus frequencies to bone
tissue response frequencies.tissue response frequencies.
 Ionic and mechanical transductive processesIonic and mechanical transductive processes
and data of electrical field effects and ofand data of electrical field effects and of
contraction frequency energetics provide a basiscontraction frequency energetics provide a basis
of support for the hypothesis of epigeneticof support for the hypothesis of epigenetic
regulation of skeletal tissue adaptation.regulation of skeletal tissue adaptation.

THE GENOMIC THESISTHE GENOMIC THESIS
 FMH – Primary role of function inFMH – Primary role of function in
craniofacial growth and development.craniofacial growth and development.
 The currently dominant scientific patternThe currently dominant scientific pattern
suggests that genomic, instead ofsuggests that genomic, instead of
epigenetic (functional) factors, regulateepigenetic (functional) factors, regulate
(cause, control) such growth.(cause, control) such growth.

Dialectical AnalysisDialectical Analysis
 Dialectic – the art or practice of arriving at theDialectic – the art or practice of arriving at the
truth by the exchange of logical arguments.truth by the exchange of logical arguments.
 The method of dialectical analysis is employed,The method of dialectical analysis is employed,
stating two opposing views – a thesis, anstating two opposing views – a thesis, an
antithesis, and a resolving synthesis basedantithesis, and a resolving synthesis based
primarily on an extensive review of the currentprimarily on an extensive review of the current
literature.literature.
 Recent version of FMH extends hierarchicallyRecent version of FMH extends hierarchically
from gross to microscopic levels and identifiesfrom gross to microscopic levels and identifies
some epigenetic mechanisms capable ofsome epigenetic mechanisms capable of
regulating genomic expression.regulating genomic expression.

Dialectical AnalysisDialectical Analysis
 The epigenetic/genomic problem is aThe epigenetic/genomic problem is a
dichotomy and dialectics is onedichotomy and dialectics is one
analytical method for its resolution.analytical method for its resolution.
 The dialectic analysis here considersThe dialectic analysis here considers
1.1. The genomic thesis andThe genomic thesis and
2.2. An epigenetic antithesis and a resolvingAn epigenetic antithesis and a resolving
synthesis.synthesis.

An Odontogenic Example of theAn Odontogenic Example of the
Genomic/Epigenetic DichotomyGenomic/Epigenetic Dichotomy
Use of vertebrate dental morphology inUse of vertebrate dental morphology in
various fields e.g. physical anthropology,various fields e.g. physical anthropology,
forensic odontology suggests to many aforensic odontology suggests to many a
rigid genomic control of odontogenesis, asrigid genomic control of odontogenesis, as
reflected in the temporally sequential, andreflected in the temporally sequential, and
spatially restricted, expression of thespatially restricted, expression of the
genomically regulated production ofgenomically regulated production of
specific molecules.specific molecules.

Data Supporting EpigeneticData Supporting Epigenetic
Regulation of OdontogenesisRegulation of Odontogenesis
 Chiclid fish are polyphyodont and canChiclid fish are polyphyodont and can
exhibit pronounced dental phenotypicexhibit pronounced dental phenotypic
plasticity.plasticity.
 Fed on hard-shelled mollusks – largeFed on hard-shelled mollusks – large
molariform teeth.molariform teeth.
 Fed on soft food – gracile, conical, non-Fed on soft food – gracile, conical, non-
molariform teeth.molariform teeth.

 Because each dental replacement cycleBecause each dental replacement cycle
involves identical odontogenic stages, itinvolves identical odontogenic stages, it
is postulated thatis postulated that
1.1. Mechanical force related to differentialMechanical force related to differential
diet hardness generates epigeneticdiet hardness generates epigenetic
signals, mechanotransductivelysignals, mechanotransductively
processed by dental papilla cells andprocessed by dental papilla cells and
2.2. These signals control at least theThese signals control at least the
temporal and spatial expression oftemporal and spatial expression of
genomic products related to thegenomic products related to the
development of differential tooth form,development of differential tooth form,
such as size and shape.such as size and shape.

Genomic ThesisGenomic Thesis
 It holds that the genome, from the moment ofIt holds that the genome, from the moment of
fertilization, contains all the informationfertilization, contains all the information
necessary to regulate (cause, control andnecessary to regulate (cause, control and
direct)direct)
1. The intranuclear formation and transcription1. The intranuclear formation and transcription
of mRNA, andof mRNA, and
2. Without the later addition of any other2. Without the later addition of any other
information, to regulate also all of theinformation, to regulate also all of the
intracellular and intercellular processes, allintracellular and intercellular processes, all
phenotypic features are ultimatelyphenotypic features are ultimately
determined by the DNA sequence of thedetermined by the DNA sequence of thewww.indiandentalacademy.comwww.indiandentalacademy.com

 Accordingly, morphogenesis is but theAccordingly, morphogenesis is but the
predetermined reading out of an intrinsicpredetermined reading out of an intrinsic
and inherited genomic organismal blueand inherited genomic organismal blue
print where, in addition to molecularprint where, in addition to molecular
synthesis the genome also regulates thesynthesis the genome also regulates the
geometric attributes of cell, tissue, organgeometric attributes of cell, tissue, organ
and organism size, shape and locationand organism size, shape and location
(e.g. from fertilized egg to embryo)(e.g. from fertilized egg to embryo)

 Genomic thesis originated with classicalGenomic thesis originated with classical
Mendelian genetics.Mendelian genetics.
 It provided theoretical basis for certainIt provided theoretical basis for certain
human eugenic theories.human eugenic theories.
 Later came the neo-Darwinian synthesis,Later came the neo-Darwinian synthesis,
a currently accepted pattern ofa currently accepted pattern of
phylogenetic regulation.phylogenetic regulation.

The Mega Human Genome ProjectThe Mega Human Genome Project
Intended toIntended to
1.1. Describe the complete human genome.Describe the complete human genome.
2.2. Demonstrate genomic controls of allDemonstrate genomic controls of all
developmental processes, at alldevelopmental processes, at all
structural levels, from the subcellular tostructural levels, from the subcellular to
the organismal.the organismal.
3.3. In a societal context, possibly lead toIn a societal context, possibly lead to
some type of eugenics.some type of eugenics.

 Many human activities are now claimed toMany human activities are now claimed to
be genomically regulated e.g. psychologicbe genomically regulated e.g. psychologic
behavior, personality, alcoholism, drugbehavior, personality, alcoholism, drug
abuse, food binging, various attentionabuse, food binging, various attention
deficiency disorders.deficiency disorders.
 Genomic control of intelligence is alsoGenomic control of intelligence is also
suggested.suggested.

Biologic Bases for the GenomicBiologic Bases for the Genomic
ThesisThesis
 Approximately only 10% of genomeApproximately only 10% of genome
seems related to phenotypicseems related to phenotypic
morphogenesis.morphogenesis.
 This 10% of DNA exists in 2 familiesThis 10% of DNA exists in 2 families
1.1. Vastly preponderant “housekeeping”Vastly preponderant “housekeeping”
genes.genes.
2.2. Non-abundant “structural” genes.Non-abundant “structural” genes.

 Housekeeping genes regulate the normalHousekeeping genes regulate the normal
molecular synthesis of agents involved inmolecular synthesis of agents involved in
1.1. Common metabolic, respiratory activities of allCommon metabolic, respiratory activities of all
cells andcells and
2.2. The specific activities of special cell types (e.g.The specific activities of special cell types (e.g.
neurons, osteoblasts, ameloblasts etc).neurons, osteoblasts, ameloblasts etc).
 These genes also regulate the synthesis of theThese genes also regulate the synthesis of the
specific molecular gene products, whosespecific molecular gene products, whose
presence, absence or abnormal molecularpresence, absence or abnormal molecular
configuration are associated with the humanconfiguration are associated with the human
pathologic conditions e.g. achondroplasia,pathologic conditions e.g. achondroplasia,
osteogenesis imperfecta etc.osteogenesis imperfecta etc.
 Such disorders provide the model on which theSuch disorders provide the model on which the
program of medical genetics is build.program of medical genetics is build.

 Alterations in genomically regulated processesAlterations in genomically regulated processes
of molecular synthesis can cause an eventualof molecular synthesis can cause an eventual
“structural collapse” at the hierarchically higher“structural collapse” at the hierarchically higher
level of a macroscopic bone.level of a macroscopic bone.
 The claim of genomic control of the molecularThe claim of genomic control of the molecular
synthesis underline the formation of suchsynthesis underline the formation of such
molecular skeletal tissue “building blocks” doesmolecular skeletal tissue “building blocks” does
not substantiates the further claim that thenot substantiates the further claim that the
genome regulates the growth and developmentgenome regulates the growth and development
(size, shape, location, histological composition)(size, shape, location, histological composition)
of the gross anatomical bone.of the gross anatomical bone.

Genomic Thesis in OrofacialGenomic Thesis in Orofacial
BiologyBiology
 Most genetic studies of cephalic or cranialMost genetic studies of cephalic or cranial
morphogenesis assumes genomic regulationmorphogenesis assumes genomic regulation
of each anatomical structure.of each anatomical structure.
 Johnston and Bronsky claimed that prenatalJohnston and Bronsky claimed that prenatal
craniofacial development is controlled by twocraniofacial development is controlled by two
interrelated, temporally sequential processesinterrelated, temporally sequential processes
1.1. Initial regulatory (homeobox gene activity)Initial regulatory (homeobox gene activity)
2.2. Subsequent activity of two regulatorySubsequent activity of two regulatory
molecular groupsmolecular groups
–– growth factor familygrowth factor family
–– steroid /thyroid/retinoid acid super family.steroid /thyroid/retinoid acid super family.

 Homeobox genes coordinate the development ofHomeobox genes coordinate the development of
the development of complex craniofacialthe development of complex craniofacial
structures.structures.
 In both normal and abnormal development,In both normal and abnormal development,
much of the regulation of the development ofmuch of the regulation of the development of
virtually all of the skeletal and connective tissuevirtually all of the skeletal and connective tissue
of the face is dependant on a cascade ofof the face is dependant on a cascade of
overlapping activity of homeobox genes.overlapping activity of homeobox genes.
 Growth factors are proteins that bind toGrowth factors are proteins that bind to
receptors on the cell surface, with the primaryreceptors on the cell surface, with the primary
result of activating cellular proliferation and/orresult of activating cellular proliferation and/or
differentiation.differentiation.

 It is claimed that regulatory moleculesIt is claimed that regulatory molecules
cancan
1.1. Alter the manner in which the homeoboxAlter the manner in which the homeobox
genes coordinate cell migration andgenes coordinate cell migration and
subsequent cell interactions that regulatesubsequent cell interactions that regulate
growth andgrowth and
2.2. Be involved in the genetic variationsBe involved in the genetic variations
causing, or contributing to, the abnormalcausing, or contributing to, the abnormal
development of relatively commondevelopment of relatively common
craniofacial malformations, perhapscraniofacial malformations, perhaps
modifying Hox gene activity.modifying Hox gene activity.

Points in critique of Genomic HypothesisPoints in critique of Genomic Hypothesis
 HierarchyHierarchy
 EmergenceEmergence
 CausationCausation
Emergence is not genomically controlled.Emergence is not genomically controlled.
Instead, the integrated activities of all theInstead, the integrated activities of all the
attributes in a given hierarchical level self-attributes in a given hierarchical level self-
organize to produce the next higher level oforganize to produce the next higher level of
complexity.complexity.
Biologic structures build themselves i.e.Biologic structures build themselves i.e.
bones do not grow, they are grown. Epigeneticbones do not grow, they are grown. Epigenetic
processes and mechanisms are regulatory ofprocesses and mechanisms are regulatory of
hierarchical organization and of emergence andhierarchical organization and of emergence and
self organization.self organization.

 Osteogenesis of left mandibular angularOsteogenesis of left mandibular angular
process ectofacial surface of 14yr oldprocess ectofacial surface of 14yr old
malemale
1.Genomic thesis – osteoblastic genome1.Genomic thesis – osteoblastic genome
2.Epigenetic antithesis – epigenetic2.Epigenetic antithesis – epigenetic
landscape.landscape.
Decisions are not predetermined byDecisions are not predetermined by
encoded genetic information.encoded genetic information.
Genomic hypothesis proposes noGenomic hypothesis proposes no
pathways from molecules topathways from molecules to
morphogenesis.morphogenesis.

 Material cause – cellular intercellularMaterial cause – cellular intercellular
materials – hardware.materials – hardware.
 Formal cause – genomic code/rules –Formal cause – genomic code/rules –
software/program.software/program.
 Efficient cause – epigenetic factors –Efficient cause – epigenetic factors –
extrinsic input (of text for article).extrinsic input (of text for article).

Gap junctionGap junction
 Opening and closing.Opening and closing.
 Factors affecting – localFactors affecting – local
environment/metabolic factors.environment/metabolic factors.
 Ca2+ and pH.Ca2+ and pH.
 Hexagonal structures. Protein connexin.Hexagonal structures. Protein connexin.
 Present singly.Present singly.

OsteoclastOsteoclast
 Arise – fusion of mononuclear cells.Arise – fusion of mononuclear cells.
 Labeling experiments with grafted cells.Labeling experiments with grafted cells.
 Similarity between two.Similarity between two.
 Monoclonal antibodies.Monoclonal antibodies.
 Common myeloid precursor.Common myeloid precursor.
 Syncytial cells dissociate.Syncytial cells dissociate.

The epigenetic antithesis andThe epigenetic antithesis and
resolving synthesisresolving synthesis
““It is a fallacy that the genome, the totality ofIt is a fallacy that the genome, the totality of
DNA molecules, is the main repository forDNA molecules, is the main repository for
developmental information i.e. that theredevelopmental information i.e. that there
exists a genetic program, or blue print,exists a genetic program, or blue print,
theoretically capable of creating an entiretheoretically capable of creating an entire
organism.”organism.”
- M. A. Corner (1994)- M. A. Corner (1994)

Biological mechanisms andBiological mechanisms and
processes.processes.
 A process is a series of actions orA process is a series of actions or
operations that lead toward a particularoperations that lead toward a particular
result.result.
 A mechanism is the fundamental physicalA mechanism is the fundamental physical
or chemical process(es) involved in oror chemical process(es) involved in or
responsible for an action, reaction, orresponsible for an action, reaction, or
other natural phenomenon.other natural phenomenon.
i.e. mechanisms underlie processes.i.e. mechanisms underlie processes.

The epigenetic antithesisThe epigenetic antithesis
 Gene: The unit of heredity: one or moreGene: The unit of heredity: one or more
nucleic acid sequences incorporatingnucleic acid sequences incorporating
information necessary for the generationinformation necessary for the generation
of a particular peptide or RNA product.of a particular peptide or RNA product.
 Genomic thesis is denied because it isGenomic thesis is denied because it is
both Reductionist and Molecular.both Reductionist and Molecular.

The epigenetic antithesisThe epigenetic antithesis
 The epigenetic antithesis details both,The epigenetic antithesis details both,
processes and mechanisms, clarifying theprocesses and mechanisms, clarifying the
causal chain between genome andcausal chain between genome and
phenotype.phenotype.

Craniofacial epigeneticsCraniofacial epigenetics
 Epigenetics refers to the entire series ofEpigenetics refers to the entire series of
interactions among cells and cell products whichinteractions among cells and cell products which
leads to morphogenesis and differentiation.leads to morphogenesis and differentiation.
 Thus all cranial development is epigenetic byThus all cranial development is epigenetic by
definition.definition.
 This view is supported by Herring and Hall.This view is supported by Herring and Hall.
 Genome may also modify/control local and gen.Genome may also modify/control local and gen.
epigenetic factors e.g. extracellular substancesepigenetic factors e.g. extracellular substances
and various hormones respectively.(??)and various hormones respectively.(??)

Epigenetic factorsEpigenetic factors
 Definition.Definition.
 Clinical orthodontic therapy.Clinical orthodontic therapy.
 Appliance – prosthetic functional matrices.Appliance – prosthetic functional matrices.
 Moss mentioned – the future aim must beMoss mentioned – the future aim must be
to elucidate the molecular, genomic,to elucidate the molecular, genomic,
mechanisms whose activation underliesmechanisms whose activation underlies
the adaptive growth processes of thethe adaptive growth processes of the
mandibular functional cranial componentsmandibular functional cranial components
(i.e. skeletal + functional matrices).(i.e. skeletal + functional matrices).

LoadingLoading
 Epigenetic process modifying DNA.Epigenetic process modifying DNA.
 Epigenetic process of loading andEpigenetic process of loading and
epigenetic mechanisms evoked by thisepigenetic mechanisms evoked by this
process.process.
 Dynamic and static loading.Dynamic and static loading.
 Mechanical loading influences geneMechanical loading influences gene
expression.expression.
 Tissue loading deforms ECM.Tissue loading deforms ECM.

Regulation of functional matricesRegulation of functional matrices
 Epigenetic control / mechanical load.Epigenetic control / mechanical load.
 Neurotrophic role.Neurotrophic role.

A resolving synthesisA resolving synthesis
““It seemed that the next minute they wouldIt seemed that the next minute they would
discover a solution. Yet it was not clear todiscover a solution. Yet it was not clear to
both of them that the end was still far, farboth of them that the end was still far, far
off, and that the hardest and mostoff, and that the hardest and most
complicated part was only just beginning.”complicated part was only just beginning.”
- Anton Chekov.- Anton Chekov.
The lady with the dog.The lady with the dog.

The resolving synthesisThe resolving synthesis
 Both genomic and epigenetic processesBoth genomic and epigenetic processes
and mechanisms are necessary causes.and mechanisms are necessary causes.
 Neither alone are sufficient cause.Neither alone are sufficient cause.
 Integrated activities.Integrated activities.
 Genomic factors – intrinsic and prior.Genomic factors – intrinsic and prior.
 Epigenetic factors – extrinsic andEpigenetic factors – extrinsic and
proximate.proximate.

ComplexityComplexity
 New emerging disciplines of complexityNew emerging disciplines of complexity
theory suggests that epigenetic processestheory suggests that epigenetic processes
and mechanisms regulate morphogenesis.and mechanisms regulate morphogenesis.
 Integrated topics – mathematics, biology,Integrated topics – mathematics, biology,
and physics. Also bioengineering andand physics. Also bioengineering and
computer science.computer science.

Complexity theoryComplexity theory
 Biological systems as “ensembles”.Biological systems as “ensembles”.
 Complex adaptive system (CAS).Complex adaptive system (CAS).
 Minor changes in epigenetic input canMinor changes in epigenetic input can
cause huge fluctuations in thecause huge fluctuations in the
morphological output.morphological output.
 Assumption – parallel processing.Assumption – parallel processing.

Complexity theoryComplexity theory
 Ontogeny involves non–linear processesOntogeny involves non–linear processes
and is not fully predictable.and is not fully predictable.
 Complexity theory makes it clear that mostComplexity theory makes it clear that most
biological systems are non linear; thusbiological systems are non linear; thus
non-linear formulations are necessary.non-linear formulations are necessary.

 The operation of complexity theory isThe operation of complexity theory is
suggested as :suggested as :
Environmental factors thus play aEnvironmental factors thus play a decisivedecisive rolerole
in all ontogenetic process. But it is thein all ontogenetic process. But it is the
organism itself that, as an integrated system,organism itself that, as an integrated system,
dictates the nature of each and everydictates the nature of each and every
developmental response … the living organismdevelopmental response … the living organism
self – organizes on the basis of its own internalself – organizes on the basis of its own internal
structuring, in continuous interaction with thestructuring, in continuous interaction with the
environment in which it finds itself.environment in which it finds itself.

 Nature Vs Nurture.Nature Vs Nurture.
 It has been thoroughly documentedIt has been thoroughly documented
that measures of the craniofacialthat measures of the craniofacial
complexes have moderate to highcomplexes have moderate to high
heritabilities, that they’re primarily aheritabilities, that they’re primarily a
consequence of “nature” rather thanconsequence of “nature” rather than
“nurture”.“nurture”.

ConclusionsConclusions
 The conceptual tension betweenThe conceptual tension between
hypotheses suggesting the regulatoryhypotheses suggesting the regulatory
primacy of either genomic (genetic) or ofprimacy of either genomic (genetic) or of
epigenetic factors and/or processes inepigenetic factors and/or processes in
morphogenesis continues unabated.morphogenesis continues unabated.
 ““It’s a win-win situation.”It’s a win-win situation.”
 Genomic and epigenetic processes areGenomic and epigenetic processes are
“apples and pears.”“apples and pears.”

ConclusionsConclusions
 Individually both are necessary causes,Individually both are necessary causes,
but neither are sufficient causes alone.but neither are sufficient causes alone.
 Together they provide both the necessaryTogether they provide both the necessary
and sufficient causes for the controland sufficient causes for the control
(regulation) of morphogenesis.(regulation) of morphogenesis.
 Epigenetic processes and events are theEpigenetic processes and events are the
immediate proximate causes ofimmediate proximate causes of
development, and as such they are thedevelopment, and as such they are the
primary agencies.primary agencies.

 Lastly,Lastly,
The fuller demonstration of exactly howThe fuller demonstration of exactly how
epigenetic events carry out their roles willepigenetic events carry out their roles will
be considered later in the context of abe considered later in the context of a
review of the implications of complexityreview of the implications of complexity
theory for the FMH.theory for the FMH.



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Functional matrix hypothesis revisited

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