Growth Factors and Bone Formation in Osteoporosis: Roles for Fibroblast Growth Factor and Transforming Growth Factor Beta

Laboratory of Osteoblast Biology and Pathology, INSERM U606, Paris, France.
Current Pharmaceutical Design (Impact Factor: 3.45). 02/2004; 10(21):2593-603. DOI: 10.2174/1381612043383773
Source: PubMed


Osteoporosis is characterised by excess bone fragility resulting from bone loss and altered bone microarchitecture. Bone loss occurring during aging and after menopause in women is known to result from an imbalance between bone formation and resorption. Bone formation is dependent on the commitment of osteoprogenitor cells, the proliferation of pre-osteoblasts, their differentiation into mature osteoblasts synthesising bone matrix and the life-span of mature osteoblasts. Transforming Growth Factor beta (TGFbeta) and Fibroblast Growth Factors (FGFs) are important factors that promote osteoprogenitor cell proliferation and osteogenesis. Reduced expression of TGFbeta in bone was found in several animal models of osteopenia. In addition, both FGF and TGFbeta were found to exert anabolic effects on bone formation in intact animals and to reduce bone loss in experimental models of osteoporosis. Both genetic manipulation of FGF and TGFbeta or their receptors in mice and bone phenotype associated with FGF receptors and TGFbeta mutations or polymorphism suggest that TGFbeta and FGF signalling may contribute to the control of osteogenesis and bone mass in vivo. The determination of molecular mechanisms involved in the anabolic actions of FGF and TGFbeta in cells of the osteoblastic lineage may lead in the future to the development of new therapeutic strategies aimed at improving bone formation in osteoporotic patients.

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    • "With long-term exposure of high doses of caffeine there is substantial accumulation of paraxanthine [65,66]. Paraxanthine has in vitro been found to be a potent suppressor of transforming growth factor beta (TGF-β) [67], which stimulates bone formation, and TGF-β deficiency may result in osteoporosis [68]. Interestingly, paraxanthine has been found to be the most powerful pharmacological repressor of hepatocellular TGF-β dependent connective tissue growth factor expression among the drug family of methylxanthines, including caffeine [67]. "
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    ABSTRACT: Drinking coffee has been linked to reduced calcium conservation, but it is less clear whether it leads to sustained bone mineral loss and if individual predisposition for caffeine metabolism might be important in this context. Therefore, the relation between consumption of coffee and bone mineral density (BMD) at the proximal femur in men and women was studied, taking into account, for the first time, genotypes for cytochrome P450 1A2 (CYP1A2) associated with metabolism of caffeine. Dietary intakes of 359 men and 358 women (aged 72 years), participants of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), were assessed by a 7-day food diary. Two years later, BMD for total proximal femur, femoral neck and trochanteric regions of the proximal femur were measured by Dual-energy X-ray absorptiometry (DXA). Genotypes of CYP1A2 were determined. Adjusted means of BMD for each category of coffee consumption were calculated. Men consuming 4 cups of coffee or more per day had 4% lower BMD at the proximal femur (p = 0.04) compared with low or non-consumers of coffee. This difference was not observed in women. In high consumers of coffee, those with rapid metabolism of caffeine (C/C genotype) had lower BMD at the femoral neck (p = 0.01) and at the trochanter (p = 0.03) than slow metabolizers (T/T and C/T genotypes). Calcium intake did not modify the relation between coffee and BMD. High consumption of coffee seems to contribute to a reduction in BMD of the proximal femur in elderly men, but not in women. BMD was lower in high consumers of coffee with rapid metabolism of caffeine, suggesting that rapid metabolizers of caffeine may constitute a risk group for bone loss induced by coffee.
    Nutrition & Metabolism 02/2010; 7(1):12. DOI:10.1186/1743-7075-7-12 · 3.26 Impact Factor
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    • "It cannot stimulate bone formation in critical sized defects by itself. Therefore, growth factors such as TGF-b [14] [15], bFGF [16], and bone morphogenetic proteins (BMPs) [17] [18] are often employed to promote bone formation. Among them, BMP-2 is a potent bone stimulator and it plays key roles in many steps during bone morphogenesis [17] [19]. "
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    ABSTRACT: Considerable research has been focused on the development of bone morphogenetic protein-2 (BMP-2) delivery system for homologous and efficient bone regeneration. The aim of the present study was to develop a collagen-based targeting bone repair system. A collagen-binding domain (CBD) was added to the N-terminal of native BMP-2 to allow it bind to collagen specifically. We showed that the collagen-binding bone morphogenetic protein-2 (named bone morphogenetic protein2-h, BMP2-h) had maintained the full biological activity as compared to rhBMP2 lacking the CBD. In vitro functional study also demonstrated that collagen matrix could maintain higher bioactivity of BMP2-h than native BMP-2. When demineralized bone matrix (DBM) impregnated with BMP2-h was implanted subcutaneously in rats, homogeneous bone formation was observed. Moreover, in a rabbit mandible defect model, surgical implantation of collagen matrix loaded with BMP2-h exhibited remarkable osteoinductive properties and excellent homogeneous bone formation. Our studies suggested that this novel collagen-based BMP-2 targeting bone repair system induced better bone formation not only in quantity but also in quality. Similar approaches may also be used for the repair of other tissue injuries.
    Biomaterials 03/2007; 28(6):1027-35. DOI:10.1016/j.biomaterials.2006.10.013 · 8.56 Impact Factor
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    • "the osteoblast life span is an important factor controlling membranous and long bone formation (Manolagas, 2000; Fromigué et al., 2004), the elucidation of mechanisms underlying integrin-mediated regulation of osteoblast survival may provide important insights into the regulation of osteogenesis. Integrin receptors are coupled to growth factor receptors and thereby regulate multiple biological functions (Miranti and Brugge, 2002). "
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    ABSTRACT: Fibroblast growth factor receptor signaling is an important mechanism regulating osteoblast function. To gain an insight into the regulatory role of FGF receptor-2 (FGFR2) signaling in osteoblasts, we investigated integrin-mediated attachment and cell survival in human calvarial osteoblasts expressing activated FGFR2. FGFR2 activation reduced osteoblast attachment on fibronectin. This was associated with reduced expression of the alpha5 integrin subunit normally expressed in human calvarial osteoblasts in vivo. Treatment with lactacystin, a potent inhibitor of proteasome, restored alpha5 integrin levels in FGFR2 mutant osteoblasts. Immunoprecipitation analysis showed that alpha5 integrin interacts with both the E3 ubiquitin ligase Cbl and ubiquitin. Immunocytochemistry revealed that alpha5 integrin colocalizes with FGFR2 and Cbl at the leading edge in membrane ruffle regions. Transfection with the 70Z-Cbl mutant lacking the RING domain required for Cbl-ubiquitin interaction, or with the G306E Cbl mutant that abolishes the binding ability of Cbl phosphotyrosine-binding domain restored alpha5 integrin levels. This suggests that Cbl-mediated ubiquitination plays an essential role in alpha5 integrin proteasome degradation induced by FGFR2 activation. Reduced alpha5 integrin expression was associated with an increased Bax/Bcl-2 ratio and increased caspase-9 and -3 activities in FGFR2 mutant osteoblasts. Forced expression of alpha5 integrin rescued cell attachment and corrected both the Bax/Bcl-2 ratio and caspase-3 and caspase-9 activities in FGFR2 mutant osteoblasts. We show that Cbl recruitment induced by FGFR2 activation triggers alpha5 integrin degradation by the proteasome, which results in reduced osteoblast attachment on fibronectin and caspase-dependent apoptosis. This identifies a functional role of the alpha5 integrin subunit in the induction of apoptosis triggered by FGFR2 activation in osteoblasts, and reveals that a Cbl-dependent mechanism is involved in the coordinated regulation of cell apoptosis induced by alpha5 integrin degradation.
    Journal of Cell Science 04/2005; 118(Pt 6):1223-32. DOI:10.1242/jcs.01679 · 5.43 Impact Factor
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