1the functional matrix hypothesis 1 moss.pdf

8/10/2019 1THE FUNCTIONAL MATRIX HYPOTHESIS 1 MOSS.pdf

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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 periodic incorporation of advances in the biomedical, bioengineering, and comp utersciences allow the creation of increasingly more com prehensive revisions of the functionalma trix hypothesis . Inclusion o f two topics, 1) the mechan isms of cellular me chanotransd uction,and 2) biolog ic netw ork theory, pe rmit this latest revision; presented here in two interrelatedarticles. In this first article, the several p oss ible types o f intracellular proce sses o fmec hanotransdu ction are described. These translate the informational content of a periostealfunctiona l m atrix stimulus into a skeletal unit bone) cell signal. The correlation between thestrengths of the endoge nous electrical f ields produced by muscle skeletal m uscle activity, andthose to which bone cells maximally respond are stressed. Further, a physical chain of

macrom olecular levers , connecting the ex tracellular matrix to the bo ne cell genome isdesc ribed, su gge sting ano ther means of epigenetic regulation of the bone cell genome,including its phe notyp ic expression . Am J Orth od Dentofac O rthop 1997;112:8-11 .)

In t roduct ion . This ser ies o f four a r t ic les 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 re n o w a f t e r a l l t h e d u s t h a s se t t l ed . " Bu t , t h e re 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 scu ss i o n o f fu n c t i o n a l ma 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 te unaw are ofTh i s i n i t s e lf i s a mo s t n o t ew o r t h y co n t r i b u t i o n ,

b ecau s e m o s t o f u s , i n b o t h t h e b a s i c an d c l i n i ca lo r t h o d o n t i c sc i en ces , a re rea l l y n o t aw are o f ad -v an ces i no ther re l ev an t fi e ld s . W e can l ea rn Th e n ,a t t h e en d , t h e re i s a l o o k a t t h e fu t u re , an d t h i s g o esc 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 an d t o d ay . In a ll , Dr. M o ss ' s a s se ssm en t o f h is o wnwo rk a s a rev i s i o n i s , I t h i n k , mo re o f a sch 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 ies .

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 , wh i ch h as a so l i d rep u t a t i o n fo r reco g n i z i n gb a l an ce , fo r a n i n t ro sp ec t i v e d i s sec t i o n o f a b i o l o g i c

c 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 co n cep t i s ev a l u a t ed i n t h e l i g h t o f p a ra l l e lb i o l o g i c t h eo ry, u n co v e re d f ro m o t h e r d i v e rse f ie l d s ,i t p re sen t s a p e rsp ec t i v e fo r o r t h o d o n t i c sch o l a r sav a i l ab l e n o wh ere e l se .

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 e

Fr om the D epar tm en t o f Ana tomy and Ce l l Biology, Co l l ege o f Phys i c i ansand Surgeons , and Schoo l o f Den ta l and O r a l Su rger y, Co lumb ia Un iver-sity.Repr in t r eques t s t o : P r o f . E mer i tu s Melv in L . Moss , Depar tmen t o fAna to my and Ce l l Bio logy, Co lumbia Un iver s i t y, 630 W. 168 th S t ., N ewYor k , NY 10032. e - mai l : moss@cucer s l . c iv i l . co lumbia . eduCopyr igh t 1997 by the Am er i can A ssoc i a t i on o f Or thodon 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 dthe 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 fu n c t i o n a l ma t r i x i s i n v o l v ed i ni 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 eas o f co mp l ex i t y an d se l f -o rg an i za t i o n p l ay 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 re l a t ed a r t ic l e s , o f wh i ch t h i s i s t h e f i r s t. Th 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 ere fe ren c e l is t fo 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 AT 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 en o m i c ) an d ex t r i n s ic (ep i g en e t i c ) f ac t o rsi n cep h a l i c g ro wt h ev o l v ed i n t o t h e fu n c t i o n a l ma-t r ix h y p o t h es i s (FM H) . 1 Th i s i n i t ia l v e r s i o n , a s au g -me n t ed , 2 an d s t re s s in g ep i g en e t i c p r i m acy (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 .

Pe r i o d i ca l l y, i n co rp o ra t i o n o f ad v an ces 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 yFM H v e rs i o n s . 5,6 An d recen t wo rk o n t wo 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 11 2 No 1

b io log ic ce l lu la r ne tw ork theory, pe rm i t t he p r esen-tatio n of this late st revision. 7-1

T H E C O N C E P T U L N D N T O M I C B S E S O F

T 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 ldindicate (a) those por t ions that are re ta ined, ex-t ende d o r d i sca rded , a nd (b ) which p r io r de f i ci en -c i es a r e now reso lved .

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 lly k now n or easily a vailable, 1'11-18 thr ee areof pa r t i cu la r r e sonance fo r th i s r ev is ion.

The developmental or igin of a l l cranial skeletalelements (e.g. , skeletal units) and all their subsequentchanges in size and shape (e.g. , form) and location, aswel l as their m aintenance in being, are a lways, wi thoutexcept ion, secondary, compensatory, and mechanical ly

obl igatory responses to the tem poral ly and ope rat ion-ally pr ior d ema nds of thei r re la ted cephal ic nonskel-etal cells, t issues, organs, and operational volumes(e.g. , the functional matrices) .

M ore p rec i se ly, the F M H c la ims tha t ep igene t i c ,ex t r aske le t a l f ac to r s and p rocesses a r e the p r io r,proximate, ext r insic , and pr imarycause of a l l adap-t ive , secondary r esponses o f ske le t a l t is sues andorgan s? I t f o llows tha t t he r esponses o f the ske le t a lun i t ( bone and ca r t i l age) ce l l s and t i s sues a r e no td i r ec tly r egu la t ed by in fo rmat iona l con ten t o f t heint r insic skeletal cel l genome per se . Rather, th is

addi t ional , ext r insic , epigenet ic informat ion is cre-a t ed b y func t iona l m at r ix o pera t ions .

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 lmat r i ces: pe r ios t ea l and capsu la r J 6'17 The fo rmer,typif ied by skeletal muscles, regulates the histologi-ca lly obse rvab leactive growth p rocesses o f ske le t a lt i ssue adaptat ion.

This new version deals only wi th the responses toper iosteal matr ices. I t now includes the molecular a ndcellular processes underlying the tr iad of active skele-ta l growth processes: deposi t ion, resorpt ion, and main-tenance. Histologic studies of actively adapting osse-

ous t i ssues demonstra te that (1) adjacent adaptat ionalt i ssue sur faces s imul taneously show deposi t ion, re-sorption, and maintenance; (2) adaptation is a t issueprocess. Deposi t ion and maintenance are funct ions ofrelatively large groups (cohorts, compartments) ofhomologous osteoblasts, never single cells; and (3) asharp demarcat ion exists between adjacent cohor ts ofactive, depository, and qu iescen t (resting) osteoblasts.

C o n s t r a i n t s o f t h e F M H

Ini tia l ly, the F M H ~,2 pro vide d onlyquali tat ivenar r a t ive desc r ip t ions o f the b io log icd y n ami cs o f

cephal ic growth, a t the gross anatomic level , and i thad two exp lana to ry cons t r a in t s : me thodo log ic andhierarchical .

1 Methodologic const ra in tM 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

Thi s penu l t imate FEM rev i s ion added ob jec t ive ,r e f e r ence- f r ame- invar i an t , f i ne -g ra ined , and con-cep tua l ly in t eg ra t ed desc r ip t ions o f the quan t i t a t iveaspec t s o f l oca l i zed cepha l i c g rowthk i n ema t i c s tothe ea r l i e r qua l i t a t ive (phenomenolog ic ) desc r ip -

t ions o f g rowthdyn am ics. 4 6 92 H ierarchical constraint H o w e v e r, e v e n t h a t

ver s ion 's desc r ip t ions d id no t ex tend dow nwa rd toprocesses a t t he ce l lu l a r, subce l lu l a r, o r molecu la rs t ruc tu ra l domains , o r ex tend upwa rds to themul t i ce l lu l a r p roc esses by which bone t i s sues r e -spond to lower l eve l signal s. Al l p r io r F M H ver s ionsw 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 -tween these tw o h ie r a r ch ica l l eve l s.

Exp l ic i tl y, t he F M H cou ld no t de sc r ibe e i the rhow ex t r ins ic , ep igene t i c FM s t imul i a r e t r ansdu cedinto reg ulatory signals by individual bo ne cel ls , or

how ind iv idua l ce l l s communica te to p roduce coor-d ina ted mul t i ce llu l a r r esponses .

At the low er ce l lu l a r o r molecu la r l eve l s, ano therp rob le m exi st s. Alm ost un i fo rmly, exper imen ta l andtheore t i ca l s tud ies o f bon e ada p ta t ion co ns ider on lythe unicel lu lar, unimolecular, or unigenomic levels .Accord ing ly, t he ir r esu l t s and der iva tive hypo these sgeneral ly are not extensible to higher mul t icel lu lar,t issue, levels.

Consequen t ly, i n p r io r F M H ver s ions , s ign if i can td i s junc t ions ex i s t be tween the desc r ip t ions a t eachof the severa l l eve ls o f bone o rgan iza tion . Such a

hiatus i s impl ici t in hierarchical theory in which theat t r ibute s o f successively higher levels are n ot s implythe sum of lower l eve l a t t r ibu tes . R a ther, a t eachh igher l eve l , new and more complex s t ruc tu ra l andopera t iona l a t t r ibu tes a r i se tha t canno t be p re -d ic t ed, even f rom a com ple te knowledge o f those o fthe lowe r levels23; e .g . , the sum of a l l lower a t -t r ibutes (biophysical , b iochemical , genomic) of ab o n e cell canno t p r ed ic t t he h igher a t t r ibu tes o f ab o n e tissue

At p resen t , no un i t a ry hypo thes i s p rov ides acomprehens ive , coheren t and in t eg ra t ed desc r ip t ion


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10 Moss merican Journa l of O rthodontics and Dentofacial OrthopedicsJuly 1997

of 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 n

All vital ceils are irritable or perturbed by andrespond 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 in t racel lu lar signal. Mechano-

transduction 33 is one type o f cellular signal transduc-tion. 34-36 The re are several mechanot rans duct 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

Static 37 and dynamic 3s 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-direct ly regulate osteoclastic resorpt ion. 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 neura l 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 us into askeletal unit cell signal for example, it moves infor-mation hierarchically downward to the osteocytes.There are two, possibly complementary, skeletalcellular mechanotransductive processes: ionic andmechanical.

Ionic or e lect r ical processes .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 themult icel lular bone cell responses. 1,42

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

St retch-act ivated channels .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 6in many othe r cell types, 25 and significantlyin fibroblasts. 4v When activated in strained os teo-cytes, they permit passage of a certain sized ion orset of ions, including K +, Ca 2+, 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 mechan icallystimulatory processes have been suggested. 52

Rough estimates of osteocytic mechanoreceptorstra in sensitivity have been made, 1,53 and the calcu-

lated values cover the morphogenetically significantstra in range of 1000 to 3000 txe in the lite rature. 54-56

Elect r ical processes .These include several, non-exclusive mechanotrans ductive 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 ec t rom echan i ca 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 ansduc t ivep r o c e s s . 5 8 5 9 6 - 62I t i s a lso possi -b l e tha t such ion ic f lows genera t e os t eocy t i cac t ion po ten t i a l s capab le o f t r ansmiss ionthrou gh gap junct 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 ccharges ex i st in bon e t i ssue , many assoc ia t edwi th the bone f lu id s ) i n the severa l osseousspac es or com par tm ents . 42,64 I t i s gen eral lyagreed that e lect r ical effects in f lu id- f i l ledbon e a r e n o t p i ezoe lec t r ic , bu t r a the r o f e lec -t rokinet ic , that is , s t ream ing poten t ia l SP)or ig i n . 42 65 66The SP is a mea sure o f thes t r a in -genera t ed po ten t i a l SG P) o f con-vec ted e l ec t r i c charges in the f lu id f low ofd 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 mV can in i t i a t e bo th os t eogenes i s andos teocy t i c ac t ionp o t e n t i a l s . 6 6 6 7

3. Electric field strength.Bone r esponds to exog-eno us elect r ical f ie lds. 68 Al thou gh the ext r in-sic e lect r ical parameter i s unclear, f ie lds t r eng th may p lay an impor t an tro l e . 69 Asigni f ican t pa ra l l e l ex i s ts be twe en the pa ram -e te r s o f these exogenou s e l ec tr i ca lf ie 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 ac tiv ity. Bo ne r esponds to exog enous e l ec -t r ical f ie lds in an effect ive range of 1 to 10ixV/cm, st rengths that are . . .on the order ofthose endogenously produced in bone tissueduring n orm al (muscle) activity 7i tal ics

mine) .Mechanical processes.Al though i t i s p robab le

that the in t racel lu lar, t ransduct ive process discussedla t e r does not in i t ia te act ion potent ia ls , i t i s an

a l t e rna tive mean s by which per ios t ea l f unc t iona lmatr ix act iv i ty ma y regula te hierarchical ly low erl evel bone ce l l genom ic func t ions .

The mechan ica l p ro per t i e s o f t he ex t r ace llu l a rmatr ix inf luence cel l behavior. 71 Lo ad ed mineral -i zed bone mat r ix t i s sue i s de fo rmed o r s t r a ined .Re cen t da ta ind ica t e tha t a se r i es o f ex tr ace l lu l a rmacromolecu la r mechan ica l l ever s ex i s t , capab le o ft r ansmi tt ing in fo rm at ion f rom the s t r a ined mat r ix tot h e b o n e c e ll n u c le a r m e m b r a n e .

The bas i s o f th i s mechan i sm i s t he phys ica lcon t inu i ty o f the t r ansm em brane molec u le in teg r in .Th i s molecu le i s connec ted ex t r ace l lu l a r ly wi th themac romo lecu la r co l l agen o f the o rgan ic mat r ix andint racel lu lar ly wi th the cytoskekeletal act in . Themolecu les o f t he l a tt e r, i n tu rn , a r e conne c ted to thenuc lea r m emb rane , a t wh ich s i te t he ac t ion o f themechan ica l l ever cha in p rev ious ly no ted in i ti a t es asubsequen t se r i es o f i n t r anuc lea r p rocesses r egu la -t o r y o f g e n o m i cac t iv i t y. 72-75See Shap i ro e tal. , 76fo rviment in , and G ree n 77 for a ge neral d iscussion ofbiophysical t ransduct ions. )

I t i s suggested that such a cytoskeletal levercha in , connec t ing to the nuc lea r membrane , canprovide a physical s t imulus able to act ivate theosteoc yt ic geno me , 78 possibly by f i r s t s t imulat ing theac t iv i ty o f such componen t s as the c fosgene s .36 ,7 3 , 78-86

I t i s by such an in t e r co nnec ted phys ica l cha in o fmolecu la r l ever s tha t pe r ios t ea l f unc t iona l mat r ixact ivi ty may regulate the genomic act iv i ty of i t sst ra ined skeletal uni t bone cel ls , including thei rpheno typ ic expression .

1the functional matrix hypothesis 1 moss.pdf

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