(SIBLING), bone sialoprotein (BSP) - Semantic Scholar


Apr 9, 2009 - Bradshaw AD, Sage EH (2001) SPARC, a matricellular protein that functions in cellular differentiation and tissue response to injury.

Author manuscript, published in "Osteoporosis International (2009) epub ahead of print" DOI : 10.1007/s00198-009-0869-2

Role of the Small Integrin Binding Ligand N­linked Glycoprotein  (SIBLING),   bone   sialoprotein   (BSP)   in   bone   development   and  remodeling.

Luc Malaval1*, Jane E Aubin2 and Laurence Vico1

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1 : INSERM U890­LBTO, 42023 Saint­Etienne, France ; IFR 143, 42023 Saint­Etienne,  France ; Université Jean Monnet, 42023 Saint­Etienne, France. 2 : Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.

* : Corrresponding author :

INSERM U890­LBTO IFR 143­IFRESIS Université Jean Monnet Faculté de Médecine 15. rue A. Paré  42023 St Etienne Cedex 02  France

T. 33­4­77­42­14­44

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Fax 33­4­77­57­55­72

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E­mail: [email protected]­st­etienne.fr

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Between cell and mineral ­ the SIBLINGs The « small, integrin binding ligand, N­linked glycoprotein » family (SIBLINGs, [1]) group  osteopontin   (OPN),   bone   sialoprotein   (BSP),   dentin   sialophosphoprotein   (DSPP),   dentin  matrix protein­1 (DMP­1) and matrix extracellular glycohosphoprotein (MEPE).  The genes  for this family are aligned on a portion of human chromosome 4 (mouse chromosome 5),  within   a   «  Bone Gene Cluster  » [2, 3] grouping other  genes  of bone interest.  Molecular  evolution   studies  [4,  5] suggest  that  SIBLINGs,  along  with  enamelins   and other  proteins 

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found   in   milk   (caseins)   and   saliva   (statherin),   form   a  «  Secretory   Calcium   binding  PhosphoProteins  » (SCPP) family  [4], sharing as a common ancestor Hevin [6], and more  precisely the long N­terminal domain that distinguishes it from the related protein SPARC  (secreted   protein,   acidic   and   rich   in   cystein)/Osteonectin   [7].   The   SCPP   share   a   flexible  structure, and many contain numerous acidic aminoacid residues, which favor interactions  with   crystals  (review  in [8]). The  SIBLINGs, more  specifically,  have acidic  pI (with  the  exception of MEPE), and display in their sequence a proline­rich stretch (basic), consensus  sites for casein­kinase, an arginine­glycine­aspartic acid (RGD) sequence binding intergrin  family receptors, and (apart for BSP) one or several ASARM (acidic serine­aspartate rich  MEPE associated) peptides, which have a high affinity for hydroxyapatite and appear to be  potent regulators of mineralization [9, 10]. The SIBLINGs also display a high degree of post­ translational modification (phosphorylation, sulfatation and/or glycosylation) which varies for  a given protein in time (cellular differentiation) and space (tissue), and directly affects their  biological functions (review in [11]). In bone, the SIBLINGs are expressed by cells of the  osteoblast lineage, DMP­1 and MEPE being mostly restricted to osteocytes. OPN and BSP at  least are also expressed by hypertrophic chondrocytes and osteoclasts. SIBLINGs are also  present   in   multiple   non­mineralized   tissues,   expecially   with   secretory   functions   (salivary 

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glands,   kidney,   [12,   13])   and   by   cancer   cells   in   which   they   favor   metastatic   processes,  particularly targeting bone (review in [14]).

Regulators of  matrix mineralization and bone remodeling DMP1  and MEPE appear as prominent regulators of mineralization. DMP1 knockout mice  display massive osteomalacia [15], at least in part indirectly, through impaired maturation of  osteocytes, which is necessary to proper mineralization, and also increased levels of FGF­23 

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(a  powerful negative  regulator  of phosphatemia  [16]) as well as  MEPE [17]. In contrast,  MEPE   knockout   increases   bone   mass   [18].   A   major   inhibitory   factor   of   mineralisation  (“Minhibin”, [19]) is the ASARM peptide (review in [9]), which is cleaved by cathepsins B  and K from MEPE and DMP­1, circulates in blood and is responsible for the high levels of  osteomalacia   observed   in   hypophosphatemia   [10].   The   most   studied   of   SIBLINGs,   OPN  (review   in   [20]),   is   a   ubiquitous   protein   whose   functions   range   from   inflammation   to  lactation, and which has been called a cytokine [21]. The bones of OPN knockout mice [22]  display   a   cell­autonomous   defect   of   osteoclast   recruitment   and   activity.   This   results   in  resorption defect, a higher trabecular bone mass in mutant bones, and a lack of response to  challenges increasing bone loss, such as ovariectomy [23] and hindlimb unloading, a model of  disuse bone loss [24]. Interacting with bone cells through both integrins (mostly α vβ 3) and  CD44,   OPN   thus   appears   directly   involved   in   the   regulation   of   cell   adhesion   and   bone  remodeling. Interestingly, OPN ­/­ bone is also hypermineralized, and lack of OPN partly  compensates osteomalacia in mice with a knockout of tissue non specific alkaline phosphatase  (TNALP),   confirming   that   OPN   also   plays   a   part   as   a  physiological   inhibitor   of   organic  matrix mineralization [25]. Considering that OPN and BSP (review in [26]) are the two major SIBLINGs expressed in bone forming osteoblasts, it is important to clarify the specificities

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and redundancies in their respective functions.

The roles of BSP ­ insights from a mild phenotype knockout We generated BSP knockout (BSP-/-) mice through genetic recombination, and studied both  their basal phenotype and their response to challenges [27]. BSP-/- mice develop and grow normally, but remain smaller than their wild-type counterparts throughout life (Figure 1a, b). Cortical bone is thinner in young mutant mice (Figure 1c) and progressively increases with

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age to reach wild type values. BSP-/- mice display early, mild matrix hypomineralization (~5% in adults), which also progressively normalizes in older mice. Previous  in vitro  data  already  showed that BSP promotes the formation of hydroxyapatite crystals, contrarily  to  OPN [28]. BSP is highly abundant in woven, primary bone [29] where it would play a direct  part in mineralization, in association with an unrelated aggregating glycoprotein, bone acidic  glycoprotein­75 [30, 31]. Indeed, primary marrow cultures from BSP­/­ bones grow normal  numbers   of   TNALP+   (=osteoblast   lineage)   colonies   but   reduced   numbers   of   mineralized  nodules respective to wild type controls. The progressive recovery of mineralization degree in  older BSP­/­ mice also suggests a role in mineralization focused on primary bone. However,  BSP­/­ marrow cultures also display reduced expression of osteoblast­related genes, such as  type   I   collagen,   indicating   that,   beyond   crystal   nucleation,   lack   of   BSP   also   affects  mineralization   through   alterations   of   the   osteoblast   phenotype   and   matrix  amount/composition. This confirms previous work with recombinant proteins, showing the  importance   of   BSP,   specifically   the   RGD   containing   portion,   for   osteoblast   phenotypic  regulation [32]. Osteoblast phenotype impairment could also explain why the bone formation  rate   (BFR)   of   secondary,   trabecular   bone   of   BSP­/­   mice   is   very   low   (Figure   1d),   with  reduced osteoblast surfaces and increased osteoid surfaces and thickness. We challenged the 

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ability of mutant mice to repair bone with a cortical defect model. After drilling a hole in the  femur proximal to the knee articulation, repair was folllowed up through histology, MRI and  microtomography.   The   lack   of   BSP   significantly   delayed   the   filling   up   of   the   defect  respective to wild­type controls, confirming the impairment of bone formation (data to be  published). Surprisingly with such low BFR, trabecular bone volume is higher (~30%) in 4  month   old   BSP­/­   long   bones   than   in   wild   type   (Figure   1c),   indicating   a   concommitant  reduction of bone resorption. Osteoclast surfaces and numbers are indeed reduced in mutant  mice (Figure 1d), and impaired osteoclast differentiation from BSP­/­ spleen and marrow cells 

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was confirmed in vitro  [27], in accordance with previous studies [33, 34]. We then asked  whether   the   low   turnover   phenotype   of   mutant   mice   could   be   increased   by   a   classical  challenge. BSP­/­ and wild type mice of both sexes were submitted to hindlimb unloading  through tail suspension for 2 to 3 weeks. We found that, contrarily to the OPN knockout [24],  mice lacking BSP lose bone under unloading, with increased BFR and osteoclast surfaces  [27]. In conclusion, BSP knockout impairs body and long bone growth and bone repair, but induces  a   high   trabecular   bone   mass   with   low   bone   turnover   that   is,   nonetheless,   responsive   to  mechanical   challenges.   These   data   clearly   contrast   with   the   phenotype   of   OPN   knockout  bone, and highlight the specificity of BSP roles in the bone context, and on a larger scale the  nonredundancy of function of SIBLING family members in skeletal biology.

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This  work  was  funded by the Canadian  Institutes  of Health  Research  (FRN83704 to J.E.  Aubin) and by the Institut National de la Santé et de la Recherche Médicale (INSERM) and  the  Centre  National  de la Recherche Scientifique  (CNRS), through both basal funding  to  affiliated laboratories and a collective grant within the Ingénierie Tissulaire­Biomécanique­ Biomatériaux   (IT2B)   INSERM/CNRS   cooperative   program.   We   gratefully   aknowledge 

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additional funding from the Société Française de Rhumatologie through a phD scholarship.

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Figure 1. Bone phenotype of BSP­/­ mice. (a) Pictures of BSP knockout (­/­) and wild type  (+/+) mice ; (b) whole radiography and (c) cortical 2D microtomography of isolated femurs  from   +/+   and   ­/­   mice   ;   (d)   quantification   of   bone   formation   rate   (BFR)   and   osteoclast  surfaces (Oc.S/BS) in the tibial trabecular bone of +/+ and ­/­ mice ; (e) 3D microtomographic  reconstruction of trabecular bone in the metaphysis of  +/+ and ­/­ femurs. The original data  were  published   in  Malaval   et   al.,   J   Exp   Med   205:1145­1153  ­   Copyright   belongs   to   the 

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authors.

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