Bone sialoprotein, but not osteopontin, deficiency impairs the mineralization of regenerating bone during cortical defect healing

Monfoulet, Laurent-Emmanuel; Malaval, Luc; Aubin, Jane E.; Rittling, Susan R.; Gadeau, Alain Pierre; Fricain, Jean-Christophe; Chassande, Olivier

doi:10.1016/j.bone.2009.09.007

Cited by 55 publications

(40 citation statements)

References 27 publications

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“…Studies that identified single factors essential for fracture healing included those using mice deficient for Bmp-2 (36), Osteopontin (37), and bone sialoprotein (38). Similar to observations in Bmp2 c/c mice (36), we also found the presence of other osteogenic factors in the bone injury sites in Fgf-9 +/− mice which could not compensate for the lack of Fgf-9.…”

Section: Discussionsupporting

confidence: 75%

Fgf-9 is required for angiogenesis and osteogenesis in long bone repair

Behr

Leucht

Longaker³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

126

128

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Bone healing requires a complex interaction of growth factors that establishes an environment for efficient bone regeneration. Among these, FGFs have been considered important for intrinsic bonehealing capacity. In this study, we analyzed the role of Fgf-9 in long bone repair. One-millimeter unicortical defects were created in tibias of Fgf-9 +/− and wild-type mice. Histomorphometry revealed that half-dose gene of Fgf-9 markedly reduced bone regeneration as compared with wild-type. Both immunohistochemistry and RT-PCR analysis revealed markedly decreased levels of proliferating cell nuclear antigen (PCNA), Runt-related transcription factor 2 (Runx2), osteocalcin, Vega-a, and platelet endothelial cell adhesion molecule 1 (PECAM-1) in Fgf-9 +/− defects. μCT angiography indicated dramatic impairment of neovascularization in Fgf-9 +/− mice as compared with controls. Treatment with FGF-9 protein promoted angiogenesis and successfully rescued the healing capacity of Fgf-9 +/− mice. Importantly, although other pro-osteogenic factors [Fgf-2, Fgf-18, and bone morphogenic protein 2 (Bmp-2)] still were present in Fgf-9 +/− mice, they could not compensate for the haploinsufficiency of the Fgf-9 gene. Therefore, endogenous Fgf-9 seems to play an important role in long bone repair. Taken together our data suggest a unique role for Fgf-9 in bone healing, presumably by initiating angiogenesis through Vegf-a. Moreover, this study further supports the embryonic phenotype previously observed in the developing limb, thus promoting the concept that healing processes in adult organisms may recapitulate embryonic skeletal development.tibia | regeneration | tissue B one healing is an efficient regenerative process resulting in newly formed bone equivalent to the original tissue. It involves the interplay of numerous factors over the well-characterized cascade of phases, including inflammation, callus formation, and remodeling (1), which recapitulate aspects of skeletal development (2, 3). Among these factors, several members of the FGF ligands, including FGF-2, -9, and -18, as well their corresponding receptors FGFR1-3, have been identified previously as having a major role during skeletal development (4-12). Although their contribution during skeletal development is well established, less is known about FGFs in fracture healing. The recent identification of different expression patterns of FGF ligands and receptors during fracture repair (13) indicates potential functions in bone regeneration. Within the group of pro-osteogenic FGF ligands, Fgf-9 has been reported to play a role during the development of skeletal vascularization (11).Skeletal vascularization of the injury site is a key step in facilitating successful bone regeneration. Angiogenesis is achieved by two hormonal pathways: the angiopoietin-and VEGF-mediated pathways (2, 14). Vegf was identified previously as a coordinator of chondrocyte growth and bone formation in growth plates of juvenile mice (15). Moreover, Vegf is released physiologically in fracture hematoma (16). C...

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Section: Discussionsupporting

confidence: 75%

Fgf-9 is required for angiogenesis and osteogenesis in long bone repair

Behr

Leucht

Longaker³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

126

128

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“…47 Thus, regulation of BSP gene transcription appears to be important for the differentiation of osteoblasts, bone matrix initial mineralization, and the formation of hydroxyapatite and the collagenous matrix (a requirement for a potential crystal nucleate). [47][48][49] In contrast, OCN is a calcium-binding protein of bone and the most abundant noncollagenous protein of mineralized tissue. 50 It is not present in the first crystal formation but in fully mineralized matrix, 38 indicating its role in the mineralization and maturation of bone tissue.…”

Section: Discussionmentioning

confidence: 90%

Smoking Modulates Gene Expression of Type I Collagen, Bone Sialoprotein, and Osteocalcin in Human Alveolar Bone

Campos

Prati

Cirano

et al. 2015

Journal of Oral and Maxillofacial Surgery

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“…A mouse model of a segmental defect with external fixation (Tay et al, 1998) has been used extensively to model nonunion but confounding factors arising from high mobility made it unsuitable for study. We therefore modified a cortical drill-hole defect (Monfoulet et al, 2010) to generate a reproducible, mechanically stable defect, where both cortical bone and endogenous bone marrow were disrupted. The higher bone mineral content, density and biomechanical strength of cortical bone in C3H mice compared with other mouse strains (Akhter et al, 2000) allows for generation of a 1 mm x 3 mm uni-cortical defect that is stabilised by the remaining cortex and will not heal without therapeutic intervention (Gao et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

MSC-seeded dense collagen scaffolds with a bolus dose of VEGF promote healing of large bone defects

Gao

Ej²,

Chua³

et al. 2013

eCM

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The functional repair of large skeletal defects remains a significant challenge to orthopaedic surgeons due to the lack of effective strategies to promote bone regeneration, particularly in the elderly. This study investigated the potential use of bone marrow derived mesenchymal stromal cells (MSC) in a dense collagen scaffold with a bolus dose of vascular endothelial growth factor (VEGF) to repair a defect in the femoral diaphysis of mice. MSC isolated from bone marrow of 4-month-old donor mice were seeded in type I collagen gels that were then compressed to form scaffolds with a fibrillar density similar to osteoid. The cells remained metabolically active in scaffolds incubated in vitro for up to 15 days and differentiated into osteoblasts that deposited calcium-phosphate mineral into the scaffold, which was quantified using micro-computed tomographic (micro-CT) imaging. When implanted in a 1 mm x 3 mm unicortical defect the MSC-loaded scaffolds were rapidly mineralised and integrated into host bone with administration of 10 ng of recombinant VEGF injected into the femoral canal at 4 days postoperative. Empty scaffolds and MSC-seeded scaffolds implanted in defects that did not receive a bolus dose of VEGF did not mineralise or integrate with native bone. The approach with MSC, hydrogels and a biologic factor already approved for human use warrants further pre-clinical investigation with a large animal model.

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Bone sialoprotein, but not osteopontin, deficiency impairs the mineralization of regenerating bone during cortical defect healing

Cited by 55 publications

References 27 publications

Fgf-9 is required for angiogenesis and osteogenesis in long bone repair

Fgf-9 is required for angiogenesis and osteogenesis in long bone repair

Smoking Modulates Gene Expression of Type I Collagen, Bone Sialoprotein, and Osteocalcin in Human Alveolar Bone

MSC-seeded dense collagen scaffolds with a bolus dose of VEGF promote healing of large bone defects

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