title: Mice lacking bone sialoprotein (BSP) lose bone after ovariectomy and display skeletal site-specific response to intermittent PTH treatment.
abstract: Bone sialoprotein (BSP) belongs to the small integrin-binding ligand, N-linked glycoprotein (SIBLING) family, whose members play multiple and distinct roles in the development, turnover, and mineralization of bone and dentin. The functions of BSP in bone remodeling are not yet well established. We previously showed that BSP knockout (BSP(-/-)) mice exhibit a higher trabecular bone volume, concomitant with lower bone remodeling, than wild-type (BSP(+/+)) mice. To determine whether bone turnover can be stimulated in the absence of BSP, we subjected BSP(+/+) and BSP(-/-) mice to catabolic [ovariectomy (OVX)] or anabolic (intermittent PTH administration) hormonal challenges. BSP(-/-) mice progressively develop hypocalcemia and high serum PTH between 2 and 4 months of age. Fifteen and 30 d after OVX, microtomography analysis showed a significant decrease of trabecular bone volume in tibiae of both genotypes. Histomorphometric parameters of bone formation and resorption were significantly increased by OVX. PTH treatment resulted in an increase of trabecular thickness and both bone formation and resorption parameters at all skeletal sites in both genotypes and a decrease of trabecular bone volume in tibiae of BSP(+/+) but not BSP(-/-) mice. PTH increased cortical thickness and bone area in BSP(+/+) but not BSP(-/-) mice and stimulated the bone formation rate specifically in the endosteum of BSP(+/+) mice and the periosteum of BSP(-/-) mice. PTH enhanced the expression of RANKL, MEPE, and DMP1 in both genotypes but increased OPG and OPN expression only in BSP(-/-) mice. In conclusion, despite the low basal turnover, both catabolic and anabolic challenges increase bone formation and resorption in BSP(-/-) mice, suggesting that compensatory pathways are operative in the skeleton of BSP-deficient mice. Although up-regulation of one or several other SIBLINGs is a possible mechanism, further studies are needed to analyze the interplay and cross-regulation involved in compensating for the absence of BSP.
authors.affiliation: Université de Lyon and Institut National de la Santé et de la Recherche Médicale Unité 890/Institut Fédératif de Recherche 143, Saint-Etienne, France.
authors.forename: Ndéye Marième
authors.initials: NM
authors.lastname: Wade-Gueye
authors.forename: Maya
authors.initials: M
authors.lastname: Boudiffa
authors.forename: Norbert
authors.initials: N
authors.lastname: Laroche
authors.forename: Arnaud
authors.initials: A
authors.lastname: Vanden-Bossche
authors.forename: Carole
authors.initials: C
authors.lastname: Fournier
authors.forename: Jane E
authors.initials: JE
authors.lastname: Aubin
authors.forename: Laurence
authors.initials: L
authors.lastname: Vico
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Lafage-Proust
authors.forename: Luc
authors.initials: L
authors.lastname: Malaval
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D016723:Bone Remodeling / Q000187:drug effects*; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D005838:Genotype; D006023:Glycoproteins / Q000378:metabolism; D006961:Hyperparathyroidism / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006996:Hypocalcemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D058574:Integrin-Binding Sialoprotein; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010052:Ovariectomy; D010281:Parathyroid Hormone / Q000494:pharmacology*; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C513308:Dmp1 protein, mouse; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C546872:Ibsp protein, mouse; D058574:Integrin-Binding Sialoprotein; C518716:Mepe protein, mouse; D010281:Parathyroid Hormone; D010750:Phosphoproteins; D053245:RANK Ligand; D012795:Sialoglycoproteins