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S P E C I L R T I C L E

T h e f u n c t i o n a l m a t r i x h y p o th e si so f m ec h a n o t r a n s du c t i o n

r e v i s i t e d 1 T h e r o l e

M e l v i n L . M o s s , D D S , P h DNew York N .Y .The per iodic incorporat ion of advances in the biomedical , b ioengineer ing, and comp utersc iences al low the creation of increasingly more com prehensive rev is ions of the funct ionalma tr ix hypothesis. Inc lusion o f two topics, 1) the mechan isms of cel lu lar me chanotransd uct ion,and 2) biolog ic netw ork theory, pe rmit this latest revision; presented here in two interrelatedarticles. In this f irst art icle, the several p oss ible types o f intracellular proce sses o fmec hanotransdu ct ion are descr ibed. These t ranslate the informat ional content of a periostealfunctiona l m atrix st imulus into a skeletal unit bone) cell signal. The correlation between thestrengths of the endoge nous electrical f ie lds produced by muscle skeletal m uscle act iv ity , andthose to which bone cel ls maximally respond are stressed. Further, a physical chain ofmacrom olecular levers, connect ing the ex tracel lu lar matr ix to the bo ne cell genome isdesc ribed, su gge sting ano ther means of epigenetic regulation of the bone cell genome,including i ts phe notyp ic expression . Am J Orth od Dentofac O rthop 1997;112:8-11 .)

In t roduc t ion . This se r i e s o f four a r t i c l e s i s ac o h e s iv e a n d c o n s t r u ct i v e p e r s p ec t iv e o f " w h e r e w ea r e n o w a f t e r a l l t h e d u s t h a s s e t t l e d . " B u t , t h e r e i sa n o t h e r i m p o r t a n t a n d I t h i n k k e y f e a t u r e a n d t h a ti s a d i s c u s s i o n o f f u n c t i o n a l m a t r i x - t y p e s t u d i e s ( b yd i f f e re n t n a m e s , p e r h a p s ) in o ther biologic discipl inestha t o therwise we probably w ould be qu i t e unaw are o fT h i s i n i t s e lf i s a m o s t n o t e w o r t h y c o n t r i b u t i o n ,b e c a u s e m o s t o f u s , i n b o t h t h e b a s i c a n d c l i n i c a lo r t h o d o n t i c s c i e n c es , a r e r e a l l y n o t a w a r e o f a d -v a n c e s i n other r e l e v a n t fi e ld s . W e c a n l e a r n T h e n ,a t t h e e n d , t h e r e i s a l o o k a t t h e f u t u r e , a n d t h i s g o e sc o n c e p t u a l l y b e y o n d a n y t h i n g w e p r e s u m e t o u n d e r -s t a n d t o d a y . I n a ll , D r . M o ss ' s a s s e s sm e n t o f h is o w nw o r k a s a r e v i s i o n i s , I t h i n k , m o r e o f a s c h o l a r l ye l a b o r a t io n , b a s e d o n a b r o a d q u i l tw o r d o f b i o l og i cu n d e r s t a n d i n g , n o w g l e a n e d f r o m a v a r ie t y o f o t h e rspec ia l t i e s .T h e r e s u r e l y i s r o o m i n o u r d i s t in g u i s h e d j o u r -n a l , w h i c h h a s a so l i d r e p u t a t i o n f o r r e c o g n i z i n gb a l a n c e , f o r a n i n t r o sp e c t i v e d i s s e c t i o n o f a b i o l o g i cc o n c e p t t h a t h a s p r o f o u n d c l i n i c a l m e a n i n g . W h e nt h a t c o n c e p t i s e v a l u a t e d i n t h e l i g h t o f p a r a l l e lb i o l o g i c t h e o r y , u n c o v e r e d f r o m o t h e r d i v e r se f ie l d s ,i t p r e se n t s a p e r sp e c t i v e f o r o r t h o d o n t i c s c h o l a r sa v a i l a b l e n o w h e r e e l s e .T h e r e a r e c o u n t le s s M o s s r e f e r e n c e s o n t h eF r o m t h e D e p a r t m e n t o f A n a t o m y a n d C e l l B i ol o g y , C o l l e g e o f P h y s i c i a nsa n d S u r g e o n s , a n d S c h o o l o f D e n t a l a n d O r a l S u r g e r y , C o l u m b i a U n i v e r -sity.R e p r i n t r e q u e s t s t o : P r o f . E m e r i t u s M e l v i n L . M o s s , D e p a r t m e n t o fA n a t o m y a n d C e l l B i o l og y , C o l u m b i a U n i v e r s i t y , 6 3 0 W . 1 6 8 t h S t ., N e wY o r k , N Y 1 0 03 2. e - m a i l : m o s s @ c u c e r s l . c i v i l . c o l u m b i a . e d uC o p y r i g h t 1 99 7 b y t h e A m e r i c a n A s s o c i a t i o n o f O r t h o d o n t i s t s .0889-5406/97/ 5.00 + 0 8/1/70662

f u n c t i o n a l m a t r i x o v e r t h e y e a r s . This i s t h e o n et h a t w i ll b e r e f e r r e d t o f o r d e c a d e s t o c o m e , a n dt he o n e g r a d u a t e s t u d e n t s n o w w i ll d i s c u s s i n t h e i rs e m i n a r s .O n e p o i n t I w o u l d h a v e l ik e d D r . M o s s t o h a v ea d d r e s s e d i n g r e a t e r d e p t h i n t h e f i n al p ag e s i s h o wt h e f u n c t i o n a l m a t r i x i s i n v o l v e d i n i t s own g r o w t ha n d d e v e l o p m e n t o n h o w i t i s c o n t r o l l e d . T h a t i s ,h o w m u c h g e n o m e a n d h o w d o t h e p r o v o c a t i v ei d e a s o f c o m p l e x i t y a n d s e l f - o r g a n i z a t i o n p l a y i n t ot h i s ? D o n a l d E n l o w

T h i s a r ti c le is p r e s e n t e d a s a s e ri e s o fi n t e r r e l a t e d a r t ic l e s , o f w h i c h t h i s i s t h e f i r s t. T h es e c o n d a r t i c le c o n t a i n s b o t h a c o m p r e h e n s i v e s u m -m a r y o f t h is l a t e s t re v i s io n o f t h e F M H a s w e l l a s th er e f e r e n c e l is t f o r b o t h a r t ic l e s .D E V E L O P M E N T O F T H E F U N C T I O N A L M A T R I XH Y P O T H E S I S F M H )

A d e c a d e ' s s t u d y o f t h e r e g u l a t o r y ro l e s o fi n t r in s i c ( g e n o m i c ) a n d e x t r i n s ic ( e p i g e n e t i c ) f a c t o r si n c e p h a l i c g r o w t h e v o l v e d i n t o t h e f u n c t i o n a l m a -t r ix h y p o t h e s i s ( F M H ) . 1 T h i s i n i t ia l v e r s i o n , a s a u g -m e n t e d , 2 a n d s t r e s s in g e p i g e n e t i c p r i m a c y ( a s d e -f i n e d i n M o s s 3 a n d H e r r in g 4 ) , b e c a m e p e e r - a c c e p t e da s o n e e x p l a n a t o r y p a ra d i g m .

P e r i o d i c a l l y , i n c o r p o r a t i o n o f a d v a n c e s i n t h eb i o m e d i c a l , b i o e n g i n e e r in g , a n d c o m p u t e r s c ie n c e sh a v e c r e a t e d m o r e c o m p r e h e n s i v e l y e x p l a n a t o r yF M H v e r s i o n s . 5,6 A n d r e c e n t w o r k o n t w o t o p i c s ,c e l l u l a r t r a n s d u c t i o n o f i n f o r m a t i o n a l s i g n a l s a n d

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American Journal of Orthodontics and Dentofacial Orthopedics ossVolume 112 No 1

b i o l o g i c c e l l u la r n e t w o rk t h e o ry , p e rm i t t h e p r e s e n -tat io n of th is late s t revis ion. 7-1T H E C O N C E P T U L N D N T O M I C B S E S O FT H E R E V I S E D F M H

A c o m p r e h e n s i b l e r e v is io n o f t h e F M H s h o u ldind ica te (a ) those po r t ions tha t a re re ta ined , ex -t e n d e d o r d i s c a rd e d , a n d (b ) w h i c h p r i o r d e f i ci e n -c i e s a r e n o w r e s o l v e d .

A l t h o u g h t h e p r i n c ip a l F M H c o n c e p t s a re e i t h e rgen era l ly k now n or easi ly a vai lable, 1'11-18 thr ee areo f p a r t i c u l a r r e s o n a n c e fo r t h i s r e v is i o n.

The deve lopmen ta l o r ig in o f a l l c ran ia l ske le ta lelements (e.g . , skeletal uni ts) and al l their subsequentchanges in s ize and shape (e.g . , form) and locat ion, aswel l as the ir m ain tenance in be ing , a re a lways , wi thou texcep t ion , secondary , compensa to ry , and mechan ica l lyob l iga to ry responses to the t em pora l ly and ope ra t ion -a lly p r io r d ema nds o f the i r re la ted cephal ic nonske l -etal cel ls , t issues , organs, and operat ional volumes(e.g . , the funct ional matrices).

M o re p r e c i s e ly , th e F M H c l a im s t h a t e p i g e n e t i c ,e x t r a s k e l e t a l f a c t o r s a n d p ro c e s s e s a r e t h e p r i o r ,p rox imate , ex t r in s ic , and p r imary cause o f a l l a d a p -t iv e , s e c o n d a ry r e s p o n s e s o f s k e l e t a l t is s u e s a n do rg a n s ? I t f o ll o w s t h a t t h e r e s p o n s e s o f t h e s k e l e t a lu n i t ( b o n e a n d c a r t i l a g e ) c e l l s a n d t i s s u e s a r e n o td i r e c tl y r e g u l a t e d b y i n fo rm a t i o n a l c o n t e n t o f t h ein t r in s ic ske le ta l ce l l genome per se . Rather , th i sadd i t iona l , ex t r in s ic , ep igene t ic in fo rmat ion i s c re -a t e d b y fu n c t io n a l m a t r ix o p e ra t i o n s .

T h e F M H p o s t u l at e s t w o t y p e s o f f u n c ti o n a lm a t r i c e s: p e r i o s t e a l a n d c a p s u l a r J 6'17 Th e fo rm e r ,typ i f i ed by ske le ta l musc les , regu la tes the h i s to log i -c a ll y o b s e rv a b l e act ive g ro w t h p ro c e s s e s o f s k e l e t a lt i s sue adap ta t ion .

Th is new vers ion dea l s on ly wi th the responses toper ios tea l mat r ices . I t now inc ludes the molecu lar a ndcel lular processes underlying the t r iad of act ive skele-ta l g rowth p rocesses : depos i t ion , reso rp t ion , and main -tenance. His tologic s tudies of act ively adapt ing osse-ous t i ssues demons t ra te tha t (1 ) ad jacen t adap ta t iona lt i s sue su r faces s imul taneous ly show depos i t ion , re -sorpt ion, and maintenance; (2) adaptat ion is a t issueprocess . Depos i t ion and main tenance a re func t ions o frelat ively large groups (cohorts , compartments) ofhomologous osteoblasts , never s ingle cel ls ; and (3) asharp demarca t ion ex i s t s be tween ad jacen t cohor t s o fact ive, deposi tory , and qu iescen t (res ting) osteoblasts .C o n s t r a i n t s o f t h e F M H

In i ti a l ly , the F M H ~,2 p ro v ide d on ly qual i tat iven a r r a t i v e d e s c r i p t io n s o f t h e b i o l o g i c d y n a m i c s o f

cephal ic g rowth , a t the g ross ana tomic l eve l , and i th a d t w o e x p l a n a t o ry c o n s t r a i n t s : m e t h o d o l o g i c a n dh ierarch ica l .

1 Methodologic cons t ra in t M a c r o s c o p i c m e a -s u r e m e n t s , w h i c h u s e th e t e c h n i q u e s o f p o i n tm e c h a n i c s a n d a r b i t r a r y r e f e r e n c e f r a m e s , e . g . ,r o e n t g e n o g r a p h i c c e p h a l o m e t r y , p e r m i t t e d o n l ym e t h o d - s p e c i f i c d e s c r i p t i o n s t h a t c a n n o t b e s t r u c -t u r a l l y d e t a i l e d . T h i s c o n s t r a i n t w a s r e m o v e d b yt h e c o n t i n u u m m e c h a n i c s t e c h n i q u e s o f t h e f i ni tee l e m e n t m e t h o d (FEM) 6 1921 a n d o f t h e r e l a t e dm a c r o a n d b o u n d a r y e l e m e n t m e t h o d s . 9,22

Th i s p e n u l t i m a t e F EM re v i s i o n a d d e d o b j e c t i v e ,r e f e r e n c e - f r a m e - i n v a r i a n t , f i n e -g ra i n e d , a n d c o n -c e p t u a l l y in t e g ra t e d d e s c r i p t io n s o f t h e q u a n t i t a t i v ea s p e c t s o f l o c a l i z e d c e p h a l i c g ro w t h k i n e m a t i c s tot h e e a r l i e r q u a l i t a t i v e (p h e n o m e n o l o g i c ) d e s c r i p -t i o n s o f g ro w t h dyn am ics. 4 6 92 H ierarchical cons traint H o w e v e r , e v e n t h a tv e r s i o n 's d e s c r i p t io n s d i d n o t e x t e n d d o w n w a rd t op ro c e s s e s a t t h e c e l l u l a r , s u b c e l l u l a r , o r m o l e c u l a rs t ru c t u r a l d o m a i n s , o r e x t e n d u p w a rd s t o t h em u l t i c e l lu l a r p ro c e s s e s b y w h i c h b o n e t i s su e s r e -s p o n d t o l o w e r l e v e l si gn al s. A l l p r i o r F M H v e r s i o n sw e r e s u s p e n d e d o r s a n d w i c h e d a s i t w e r e , b e -t w e e n t h e s e t w o h i e r a r c h ic a l l e ve l s.

Ex p l ic i tl y , t h e F M H c o u l d n o t d e s c r i b e e i t h e rh o w e x t r in s ic , e p i g e n e t i c F M s t im u l i a r e t r a n s d u c e din to reg u la to ry s igna l s by ind iv idua l bo ne ce l l s , o rh o w i n d i v i d u a l c e l l s c o m m u n i c a t e t o p ro d u c e c o o r -d i n a t e d m u l t i c e ll u l a r r e s p o n s e s .

A t t h e l o w e r c e l lu l a r o r m o l e c u l a r l e ve l s, a n o t h e rp ro b l e m e xi st s. A l m o s t u n i fo rm l y , e x p e r i m e n t a l a n dt h e o re t i c a l s t u d i e s o f b o n e a d a p t a t i o n c o n s i d e r o n l ythe un ice l lu la r , un imolecu lar , o r un igenomic l eve l s .A c c o rd i n g l y , t h e ir r e s u l t s a n d d e r i v a ti v e h y p o t h e s e sgenera l ly a re no t ex tens ib le to h igher mul t i ce l lu la r ,t issue, levels .

C o n s e q u e n t l y , i n p r i o r F M H v e r s i on s , s i g n if i ca n td i s j u n c t i o n s e x i s t b e t w e e n t h e d e s c r i p t i o n s a t e a c ho f t h e s e v e ra l l e v e ls o f b o n e o rg a n i z a ti o n . S u c h ah ia tus i s imp l ic i t in h ie ra rch ica l theo ry in wh ich thea t t r ibu te s o f success ive ly h igher l eve l s a re n o t s implyt h e s u m o f lo w e r l e v e l a t t r i b u te s . R a t h e r , a t e a c hh i g h e r l e v e l , n e w a n d m o re c o m p l e x s t ru c t u r a l a n do p e ra t i o n a l a t t r i b u t e s a r i s e t h a t c a n n o t b e p r e -d i c t e d, e v e n f ro m a c o m p l e t e k n o w l e d g e o f t h o s e o fthe lowe r l eve l s23 ; e .g . , the sum of a l l lower a t -t r ibu tes (b iophys ica l , b iochemica l , genomic) o f ab o n e cell c a n n o t p r e d i c t t h e h i g h e r a t t r i b u t e s o f ab o n e t issue

A t p re s e n t , n o u n i t a ry h y p o t h e s i s p ro v i d e s ac o m p re h e n s i v e , c o h e re n t a n d i n t e g ra t e d d e s c r i p t i o n

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10 Mos s merican Journa l of O rthodontics and Dentofacial OrthopedicsJuly 1997of al l the processes and mechanisms involved inbone growth, remodeling, adaptation, and mainte-nance at all structural levels. This newest FMHversion, presented herein, transcends some hierar-chical constraints and permits seamless descriptionsat, and between, the several levels of bone structureand operation- from the genomic to the organ level.It does so by the inclusion of two complementaryconcepts: (1) that mechanotransduction occurs insingle bone cells, and (2) that bone cells are com-putational elements that function multicellularly asa connected cellular network.

It is useful to present the database and derivativetheories, supportive of the inclusion of these twoconcepts individually in a series of two coordinatedarticles: the first on mechanotransduction and thesecond on connected cellular networks.

e c h a n o t r a n s d u c t i o nAll vital ceils are irritable or perturbed by and

respond to alterations in their external environment.Mechanosensing processes enable a cell to senseand to respond to extrinsic loadings, a widespreadbiologic attr ibute, 24-32 by using the processes ofmechanoreception and of mechanotransduction.The former transmits an extracellular physical stim-ulus into a receptor cell; the latter transduces ortransforms the stimulus's energetic and/or informa-tional content into an i n t r ac e l lu la r signal. Mechano-transduction33 is one type of cellular signal transduc-tion. 34-36 The re are several mechanot ransduct iveprocesses, for example, mechanoelectrical andmechanochemical. Whichever are used, bone adap-tation requires the subsequent intercellular trans-mission of the transduced signals.O s s e o u s e c h a n o t r a n s d u e t i o n

Static37 and dynamic3s loadings are continuouslyapplied to bone tissues, tending to deform bothextracellular matrix and bone cells. When an appro-priate stimulus parameter exceeds threshold values,the loaded tissue responds by the triad of bone celladaptation processes. Both osteocytes and osteo-blasts are competent for intracellular stimulus re-ception and transduction and for subsequent inter-cellular signal transmission. Osteoblasts directlyregulate bone deposition and maintenance and in-directly regulate osteoclastic resorption. 39,4

Osseous mechanot ransduction is unique in fourways: (1) Most other mechanosensory cells arecytologically specialized, but bone cells are not; (2)one bone-loading stimulus can evoke three adapta-tional responses, whereas nonosseous processes

generally evoke one; (3) osseous signal transmissionis aneural, whereas all other mechanosensationalsignals use some afferent neural pathways28.41; and,(4) the evoked bone adaptational responses areconfined within each bone organ independently,e.g., within a femur, so there is no necessary inter-bone or organismal involvement.

This process translates the information contentof a periosteal functional matrix s t i m u l u s into askeletal unit cell s ignal for example, it moves infor-mation hierarchically downward to the osteocytes.There are two, possibly complementary, skeletalcellular mechanotransductive processes: ionic andmechanical.

Ion ic o r e l e c t r i c a l p r oc e s s e s . This involves someprocess(es) of ionic transport through the bone cell(osteocytic) plasma membrane. There is a subse-quent intercellular transmission of the created ionicor electrical signals that, in turn, are computed bythe operation of an osseous connected cellularnetwork (CCN), as described in the second article inthis series. That network's output regulates themulticellular bone cell responses. 1,42

Although no consensual agreement exists, osteo-cytic, ionic-mechanotransduction may involve sev-eral, possibly parallel, cellular processes.

S t r e t c h -ac t i v a te d c hanne l s . Several types of defor-mation may occur in strained bone tissue. One ofthese involves the plasma membrane stretch-acti-vated (S-A) ion channels, a structure found in bonec e l l s 4 3 - 4 6 in many other cell types,25 and significantlyin fibroblasts. 4v When activated in strained osteo-cytes, they permit passage of a certain sized ion orset of ions, including K +, Ca2+, Na +, and CS+. 46 48-50

Such ionic flow may, in turn, init iate intracel lularelectrical events, for example, bone cell S-A chan-nels may modulate membrane potential as well asCa 2+ ion fluxY 5~ Other bone cell mechanicallystimulatory processes have been suggested.52

Rough estimates of osteocytic mechanoreceptorstrain sensitivity have been made, 1,53 and the calcu-lated values cover the morphogenetically significantstrain range of 1000 to 3000 txe in the literature. 54-56

Ele c t r i c a l p r oc e s s e s . These include several, non-exclusive mechanotransductive processes (e.g., elec-tromechanical and electrokinetic), involving theplasma membrane and extracellular fluids. Electricfield strength may also be a significant pa ra me te rF

1 . E l e c t r o m e c h a n i c a l . As in most cells, the osteo-cytic plasma membrane contains voltage-acti-vated ion channels, and transmembrane ionflow may be a significant osseous mechano-

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American Journal of Orthodontics and Dentofacial Orthopedics MossVolume 112, No 1

t r a n s d u c t i v e p r o c e s s . 5 8 5 9 6 - 62 I t i s a l so poss i -b l e t h a t s u c h i o n i c f l o w s g e n e ra t e o s t e o c y t i ca c t i o n p o t e n t i a l s c a p a b l e o f t r a n s m i s s io nth rou gh gap junc t ions . 63

2. Electrokinetic. B o u n d a n d u n b o u n d e l e c t r i cc h a rg e s e x i st in b o n e t i ss u e , m a n y a s s o c i a t e dw i t h t h e b o n e f l u i d s ) i n t h e s e v e ra l o s s e o u sspac es o r com par tm en ts . 42,64 I t i s gen era l lyag reed tha t e lec t r i ca l e f fec t s in f lu id - f i l l edb o n e a r e n o t p i e z o e l e c t r ic , b u t r a t h e r o f e le c -t rok ine t ic , tha t is , s t ream ing po ten t ia l SP)o r i g i n . 4 2 6 5 6 6 Th e S P is a m e a s u re o f t h es t r a i n -g e n e ra t e d p o t e n t i a l S G P ) o f c o n -v e c t e d e l e c t r i c c h a rg e s i n t h e f l u i d f l o w o fd e f o r m e d b o n e . T h e u s u a l ly o b s e rv e d S P G o f+ 2 m V c a n i n i t i a t e b o t h o s t e o g e n e s i s a n do s t e o c y t i c a c t i o n p o t e n t i a l s . 6 6 6 7

3. Electric field strength. B o n e r e s p o n d s t o e x o g -eno us e lec t r i ca l f i e lds . 68 Al thou gh the ex t r in -s ic e lec t r i ca l parameter i s unc lear , f i e lds t r e n g t h m a y p l a y a n i m p o r t a n t r o l e . 6 9 As i g ni f ic a n t p a r a l l e l e x i s ts b e t w e e n t h e p a r a m -e t e r s o f th e s e e x o g e n o u s e l e c tr i c a l f i e lds 68,69a n d t h e e n d o g e n o u s f i e ld s p r o d u c e d b y m u s -c l e a c ti v it y . B o n e r e s p o n d s t o e x o g e n o u s e l e c -t r i ca l f i e lds in an e f fec t ive range o f 1 to 10ixV/cm, s t reng ths tha t a re . . . on the order o fthose endogenously produced in bone tissueduring n orm al (muscle) activity 7 i tal icsm i n e ) .

Mechanical processes . A l t h o u g h i t i s p ro b a b l etha t the in t race l lu la r , t ransduct ive p rocess d i scussedl a t e r d o e s no t in i t i a te ac t ion po ten t ia l s , i t i s an

a l t e rn a ti v e m e a n s b y w h i c h p e r i o s t e a l f u n c t i o n a lmat r ix ac t iv i ty ma y regu la te h ie ra rch ica l ly low erl e v el b o n e c e l l g e n o m i c fu n c t i o n s .

Th e m e c h a n i c a l p ro p e r t i e s o f t h e e x t r a c e ll u l a rmat r ix in f luence ce l l behav io r . 71 Lo ad ed minera l -i z e d b o n e m a t r i x t i s s u e i s d e fo rm e d o r s t r a i n e d .R e c e n t d a t a i n d i c a t e t h a t a s e r i e s o f e x tr a c e l lu l a rm a c ro m o l e c u l a r m e c h a n i c a l l e v e r s e x i s t , c a p a b l e o ft r a n s m i tt i n g i n fo rm a t i o n f ro m t h e s t r a i n e d m a t r i x tot h e b o n e c e ll n u c le a r m e m b r a n e .

Th e b a s i s o f th i s m e c h a n i s m i s t h e p h y s i c a lc o n t i n u i t y o f t h e t r a n s m e m b ra n e m o l e c u l e i n te g r in .Th i s m o l e c u l e i s c o n n e c t e d e x t r a c e l l u l a r l y w i t h t h em a c ro m o l e c u l a r c o l l a g e n o f t h e o rg a n i c m a t r ix a n din t race l lu la r ly wi th the cy toskekele ta l ac t in . Them o l e c u l e s o f t h e l a tt e r , i n tu rn , a r e c o n n e c t e d t o t h en u c l e a r m e m b ra n e , a t w h i c h s i te t h e a c t i o n o f th em e c h a n i c a l l e v e r c h a in p r e v i o u s l y n o t e d i n i ti a t e s as u b s e q u e n t s e r i e s o f i n t r a n u c l e a r p ro c e s s e s r e g u l a -t o r y o f g e n o m i c a c t i v i t y . 7 2- 75 S e e S h a p i ro e t al . , 76 fo rv imen t in , and G ree n 77 fo r a ge nera l d i scuss ion o fb iophys ica l t ransduct ions . )

I t i s sugges ted tha t such a cy toske le ta l l everc h a i n , c o n n e c t i n g t o t h e n u c l e a r m e m b ra n e , c a nprov ide a phys ica l s t imu lus ab le to ac t iva te theos teoc y t ic geno me , 78 poss ib ly by f i r s t s t imu la t ing thea c t i v i t y o f s u c h c o m p o n e n t s a s t h e c fo sge ne s .36 ,7 3 , 78 -86

I t i s b y s u c h a n i n t e r c o n n e c t e d p h y s ic a l c h a in o fm o l e c u l a r l e v e r s t h a t p e r i o s t e a l f u n c t i o n a l m a t r i xac t iv i ty may regu la te the genomic ac t iv i ty o f i t ss t ra ined ske le ta l un i t bone ce l l s , inc lud ing the i rp h e n o t y p i c e x p re s si o n .