FUNCTIONAL MATRIX

THEORY REVISITED

Presented by: Dr H M Manisha

PG 1st year
 CONTENTS
• FUNCTIONAL MATRIX THEORY OVERVIEW
• CONSTRAINTS OF THE FMH
• MECHANOTRANSDUCTION
• ROLE OF OSSEOUS CONNECTED CELLULAR NETWORK (CCN)
• THE GENOMIC THESIS
• THE EPIGENETIC ANTITHESIS AND THE RESOLVING SYNTHESIS
• REFERENCES
• BIBILIOGRAPHY
 FUNCTIONAL MATRIX THEORY
The developmental origin of all cranial skeletal elements (e.g., skeletal units) and
all their subsequent changes in size and shape (e.g., form) 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 nonskeletal cells, tissues,
organs, and operational volumes (e.g., the functional matrices).
 FUNCTIONAL CRANIAL COMPONENT

SKELETAL UNIT FUNCTIONAL MATRIX

MACROSKELETAL MICROSKELETAL PERIOSTEAL CAPSULAR

UNIT UNIT MATRIX MATRIX

TRANSFORMATION

TRANSLATION

GROWTH
 THE FUNCTIONAL MATRIX THEORY
REVISITED
The periodic incorporation of advances in the biomedical, bioengineering, and
computer sciences allowed the creation of increasingly more comprehensive
revisions of the functional matrix hypothesis.
A series of four articles were published addressing:
1. The role of mechanotransduction
2. The role of osseous connected cellular network
3. The genomic thesis
4. The epigenetic antithesis and the resolving synthesis
 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

1. Methodologic constraints

2. Hierarchical constraints
 METHODOLOGIC CONSTRAINTS

Macroscopic measurements, which use the techniques of point mechanics and arbitrary reference
frames, e.g., roentgenographic cephalometry, permitted only method-specific descriptions that
cannot be structurally detailed.
This constraint was removed by the continuum mechanics techniques of the finite element
method (FEM) and of the related macro and boundary element methods.

This method added quantitative aspects of localized cephalic growth kinematics to the earlier qualitative description
of growth dynamics.
 HIERARCHICAL CONSTRAINTS
The prior explanations were suspended between the two hierarchial levels, i.e. the cellular
and multicellular (tissue) level. The epigenetic or sum of all lower attributes (biophysical,
biochemical, genomic) could not explain or predict the higher attribute of the bone tissue.
The new version of FMH tries to bridge the gap between hierarchical constraints and
explains the operation from genome to organ level by two concepts:
1. Mechanotransduction occurring in single cells.
2. That bone cells function multicellularly as a connected cellular network.
 MECHANOTRANSDUCTION

Mechanotransduction is the process by which a mechanical stimulus is converted into a biologic

signal to affect a cellular response.
 OSSEOUS MECHANOTRANSDUCTION

Bone is subjected to constant loading, both static and dynamic. This is essential for
normal homeostasis of bone. When the threshold value of the force is exceeded,
the loaded tissue responds to the stimulus by the triad of bone cell adaptation. The
triad includes bone deposition and maintenance and bone resorption. Both
osteoblasts and osteocytes are competent for intracellular stimulus reception and
transduction.
The osseous mechanotransduction has four unique properties:

1. Bone cells are not cytologically specialized like other mechanosensory cells.

2. Single bone loading stimulus evokes three adaptational responses, whereas non-
osseous process generally evoke one.

3. Osseous signal transmission is aneural; it does not involve neural pathways unlike
other mechanosensory signals.

4. The adaptational response is confined within the individual bone.

Mechanotransduction translates the information content of a periosteal functional matrix
stimulus into a skeletal unit cell signal, for example, it moves information hierarchically
downward to the osteocytes.

There are two, possibly complementary, skeletal cellular mechanotransductive processes:

1. Ionic
2. Mechanical
 IONIC PROCESS
Involves some processes of ionic transport through the osteocytic plasma membrane.
There is a subsequent intercellular transmission of the created ionic or electrical signals
that are computed by the operation of an osseous connected cellular network (CCN).
CNN’s output regulates the multicellular bone cell responses.

Stretch-activated channels: a structure found in many cell types, and significantly in

fibroblasts. When activated in strained osteocytes, they permit passage of a certain sized
ion or set of ions, including K +, Ca 2+, Na +, and CS+. Such ionic flow may initiate
intracellular electrical events.
 ELECTRICAL PROCESSES

1. Electromechanical: the osteocytic plasma membrane contains voltage-activated ion

channels, and transmembrane ion flow may be a significant osseous mechano-transductive
process.
2. Electrokinetic: Bound and unbound electric charges exist in bone tissue, many associated
with the bone fluid(s) in the several osseous spaces or compartments. The strain-generated
potential (SGP) of convected electric charges in the fluid flow of deformed bone can initiate
both osteogenesis and osteocytic action potentials.
3. Electric field strength: Bone responds to exogenous electrical fields.
 MECHANICAL PROCESSES

The basis for mechanical process is the physical conductivity of the

transmembrane molecule integrin. This molecule is connected extracellularly with
the macromolecular collagen of the organic matrix and intracellularly with
cytoskeletal actins. Actins, in turn are connected to the nuclear membrane where
the mechanical action induces a series of intranuclear processes.
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, including their phenotypic expression.
 ROLE OF OSSEOUS CONNECTED
CELLULAR NETWORK (CCN)

After the initial mechanotransduction, wherein the external stimulus is converted

into intracellular mechanosensation, Moss tries to explain the intercellular
transmission of the signal through the connected cellular network hypothesis.
 BONE AS AN OSSEOUS CONNECTED
CELLULAR NETWORK
All bone cells, except osteoclasts, are extensively interconnected by gap junctions
that form an osseous CCN. Each osteocyte, enclosed within its mineralized lacuna,
has many cytoplasmic (canalicular) processes that interconnect with similar
processes of up to 12 neighboring cells. These processes lie within its canaliculi.
The small space between the cell process, plasma membrane and the canalicular
wall is filled macromolecular complexes.
Gap junctions are found where the plasma membranes of a pair of markedly
overlapping canalicular processes meet.

SUPERFICIAL OSTEOBLAST SUPERFICIAL OSTEOBLAST

PERIOSTEAL AND ENDOSTEAL OSTEOBLASTS PERIOSTEAL AND ENDOSTEAL OSTEOBLASTS

PRE-OSTEOBLASTIC CELLS PRE-OSTEOBLASTIC CELLS

In addition to permitting the intercellular transmission of ions and small molecules, gap
junctions exhibit both electrical and fluorescent dye transmission. Gap junctions are
electrical synapses and they permit bidirectional signal traffic, e.g., biochemical, ionic.

Mechanotransductively activated bone cells, e.g., osteocytes, can initiate membrane action
potentials capable of transmission through interconnecting gap junctions.
STIMULI INITIAL LAYER CELLS- LOADING

SUMMATION

INTRACELLULAR SIGNAL- MECHANOTRANSDUCTION

HIDDEN CELL LAYER (ADJACENT TO OSTEOCYTES

FINAL LAYER- OSTEOBLAST

OUTPUT

NETWORK THEORY
The outputs of these anatomically superficial cells determines the site, rate, direction,
magnitude, and duration of the specific adaptive response, i.e., deposition, resorption,
and/or main tenance, of each cohort of osteoblasts.

The CCNs show oscillation, i.e., iterative reciprocal signaling (feedback) between layers.
This attribute enables them to adjustively self-organize.

These network attributes are not reducible, i.e., they are neither apparent nor predictable
from a prior knowledge of the attributes of individual cells.

Gap junctions, permitting bidirectional flow of information, are the cytological basis for the
oscillatory behavior of a CCN.
Moss has outlined the following features of CCN:
1. Developmentally, skeletal CCN is an untrained, self organized, self adapting and
epigenetically regulated system.

2. Operationally it is a stable, dynamic system that exhibits oscillatory behavior permitting

feedback.

3. Structurally, an osseous CCN is non modular, i.e. the variations in its organization permit
discrete processing of differential signals.
The morphogenetic primacy of periosteal functional matrices on their skeletal units is
consensually accepted. As a muscular demand alters, e.g., myectomy, myotomy,
neurectomy, exercise, hypertrophy, hyperplasia, atrophy, augmentation, or repositioning, the
triad of active bone growth processes correspondingly adapts the form of its specifically
related skeletal unit.
The ability of periosteal functional matrices to regulate the adaptive responses are related to
several factors:
(a) normal muscle function strains attached bone tissue intermittently.
(b) The dynamics of skeletal muscle contraction fit rather nicely with the energetic
requirements for bone cell responsiveness.
(c) the range of specific strainfrequency harmonics of muscle dynamics are also those found to
be morphogenetically competent (i.e., osteoregulatory).
(d) normal skeletal muscle activity produces intraosseous electric fields on the order of
extrinsic fields found to be similarly morphogenetic.
(e) bone cells may be stimulated by two mechanisms:
- directly by strain activated plasma membrane channels
- indirectly by electrokinentic phenomena.
 HIERARCHIAL
CONVERSIONS OF
FUNCTIONAL
STIMULI
The epigenetic/genomic problem is a dichotomy, and dialectics is one analytical method
for its resolution.
The method consists of the presentation of two opposing views, a thesis and an
antithesis, and of a resolving synthesis. Such a dialectic analysis is presented here in two
interrelated articles that respectively consider
(1) the genomic thesis
(2) an epigenetic antithesis and a resolving synthesis.
 THE GENOMIC THESIS
The genomic thesis holds that the genome, from the moment of fertilization, contains all the
information necessary to regulate (cause, control, direct)
(1) the intranuclear formation and transcription of mRNA
(2) importantly, without the later addition of any other information,
to regulate also all of the intracellular and intercellular processes of subsequent, and
structurally more complex, cell, tissue, organ, and organismal morphogenesis.
“All (phenotype) features are ultimately determined by the DNA sequence of the genome. ''
The genomic thesis originated with classical (chromosomal) Mendelian genetics.

Later, the blending of the classical chromosomal and vertebrate paleontological

disciplines created the neo-Darwinian synthesis, a currently accepted paradigm of
phylogenetic regulation.
 THE BIOLOGIC BASIS FOR THE
GENOMIC THESIS
The somatic cells of an individual metazoan inherit two classes of molecular information:
(1) an identical diploid DNA
(2) the maternal cytoplasmic constituents of the egg: e.g., mitochondria, cytoskeleton,
membranes.
Only approximately 10% of the genome seems related to phenotypic ontogenesis.
The encoding 10% of the DNA exists in two families; the vastly preponderant
"housekeeping“ genes and the nonabundant "structural" genes.
These genes 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 non-classic
inheritance, such as Marfan syndrome, achondroplasia, osteogenesis imperfecta,
and Duchenne muscular dystrophy et cetera.
 THE GENOMIC THESIS IN OROFACIAL
BIOLOGY
Prenatal craniofacial development is controlled by two interrelated, temporally
sequential, processes:
(1) initial regulatory (homeobox) gene activity
(2) subsequent activity of two regulatory molecular groups: growth factor
families and steroid/thyroid/retinoic acid super-family.
 CRITICAL DEFINITIONS

Epigenetics: It is defined as the sum of all of the extrinsic factors impinging on

vital structure including mechanical loading and electroelectric states and all of the
intrinsic biophysical, biomechanical, biochemical and bioelectric
microenvironmental events occurring on, in, and between individual cells,
extracellular materials, and cells and extracellular substances.
• Hierarchy: Biologic structures are hierarchically organized with structural and
functional complexity increasing "upward" from the level of subatomic particles to
protons, electrons, atoms, molecules, subcellular organelles and on to cells, tissues,
organs and organisms.

• Emergence: Emergence consists of the appearance, at each successively higher and

structurally and/or operationally more complex level of new attributes or properties not
present in the lower levels, whose existence or function could not in any way be
predicted, even from a complete knowledge of all the attributes and properties of any or
all of the preceding lower organization level.
Causation: Is concerned with how the attributes of a given biologic structural level
"cause" (control, regulate, determine) the attributes of the next higher level.
They may be categorized as
Intrinsic (material & formal)
Extrinsic (efficient).
Material & formal cause are classified as "prior" causes which mean existing before the
creation of some specific state or structure. They are intrinsic because they reside within
the vital structure intra and intercellularly.
Efficient cause is proximate, i.e. its operation immediately causes the creation of a new
state. Efficient causes are extrinsic and they represent the epigenetic mechanisms.
The genomic thesis claims that the genome contains all the information needed for
growth and development of an organism from intrauterine life to senescence.
The propronents of this theory argue that “ all (phenotype) features are ultimately
determined by DNA sequence of the genome”.
 THE EPIGENETIC ANTITHESIS AND THE
RESOLVING SYNTHESIS
Process: A process is a series of activities or operations that lead towards a
particular result.

Mechanism: A mechanism is the fundamental physical or chemical process

involved in or responsible for an action-reaction or the natural phenomenon. A
mechanism stimulates a process.
Examples of epigenetic mechanisms that control the genome
- loading a femur is an epigenetic process: the possible resultant modification(s) of
bone cell DNA or of chondrocytic DNA are epigenetic mechanisms

- the specific steps of the activation and deactivation of appropriate portions of the
bone cell genome, associated with the trio of possible osteoblastic responses to loading
(deposition, resorption, or maintenance of bone tissue) is example of epigenetic
mechanism.
 THE EPIGENETIC ANTITHESIS

The epigenetic antithesis, detailing both processes and mechanisms, is integrative,

seeking to clarify the causal chain between genome and phenotype.

Its goal is to identify and describe comprehensively the series of initiating

biological processes and their related underlying (biochemical, biophysical)
responsive mechanisms that are effective at each hierarchical level of increasing
structural and operational complexity.
 CRANIOFACIAL EPIGENETICS

In terms of clinical orthodontics, and of the FMH, all therapy is applied

epigenetics, and all appliances (and most other therapies) act as prosthetic
functional matrices.
Clinical therapeutics includes a number of epigenetic processes, whose prior
operations evoke a number of corresponding epigenetic mechanisms. These latter,
in turn, underlie the observed processes of tissue adaptations by both skeletal units
and functional matrices.
 EPIGENETIC PROCESS OF LOADNIG

Different epigenetic processes can evoke mechanism capable of modifying DNA.

e.g. mechanical loading
1.Loads may act at:
- cellular level
- tissue level
2.Loads may be
-dynamic (muscle contraction)
- static (gravity)
Clinically musculoskeletal loading causes
- Both articular cartilage intercellular molecular synthesis and mineralization.
- Osteoblastic gene expression.

Epigenetic mechanism at cellular level

- Deformation of extracellular matrix
- Altering the cell shape
 REGULATION OF FUNCTIONAL
MATRICES
Periosteal functional matrices are under closely similar epigenetic control.
Mechanical loads regulate skeletal muscle (periosteal functional matrix) phenotype
and chronic muscle stimulation can change its phenotype.
 A RESOLVING SYNTHESIS

Morphogenesis is regulated (controlled, caused) by the activity of both genomic

and epigenetic processes and mechanisms. 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.
 REFERENCES
1. Moss ML. The functional matrix. In: Kraus B, Reidel R, editors. Vistas in orthodontics.
Philadelphia: Lea and Febiger, 1962:85-98.
2. Moss ML. Twenty years of functional cranial analysis. Am J Orthod 1972;61:47985.
3. Moss ML. Genetics, epigenetics and causation. Am J Orthod 1981;80:366-75.
4. Moss, Functional matrix hypothesis revisited- Am J Orthod Dentofac Orthop, 1997 july-oct
5. The functional matrix revisited.1. The role of mechanotransduction. AJODO –1997 ; 112 :8-11. •
6. The functional matrix revisted 2. The role of an osseous connected cellular network AJODO
-1997; 112:221-6
7. The functional matrix revisited.3 .The genomic thesis AJODO-1997;112:338-42
8.The functional matrix revisited.4 .The epigenetic antithesis AJODO-1997;112:410-7
 BIBILIOGRAPHY
• Orthodontics: diagnosis and management of malocclusions and dentofacial deformities
• Textbook of craniofacial growth: Sreedhar Premkumar