Growth factors and bone formation in osteoporosis: Roles for fibroblast growth factor and transforming growth factor beta
ABSTRACT 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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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 · 8.31 Impact Factor
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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 · 5.33 Impact Factor
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ABSTRACT: The present review is intended to summarize studies on the effects of palygorskite on chemical and physico-chemical properties of soils carried out in recent years, and to discuss future research required in this area. When palygorskite-containing soils are involved in irrigation practices, release of Mg from palygorskite into the soil solution will occur. Magnesium as an exchangeable cation, in turn, is known to decrease aggregate stability and to enhance the dispersivity of the soil clay fractions. Knowledge of factors affecting rheological properties of soil clay suspensions is essential for the understanding of mechanisms of water and solid-particle transfer through the soil profile. The rheological behaviour of soil clay suspensions is, however, complex and cannot be predicted from that of suspensions of standard clays. Although the flocculation value (FV) of palygorskite at near neutral pH is significantly lower than that of smectite, the presence of palygorskite in the soil clay fraction will not affect the FV of the soil clay since smectite, which is always present in the clay fraction of palygorskite-containing soils, has a dispersive effect on palygorskite. Palygorskite has the strongest disaggregation potential and the highest ability to migrate in the soil among common phyllosilicates such as smectite and kaolinite. Palygorskite particles are thus likely to move preferentially over smectite and kaolinite downwards in the soil profile, and eventually to clog soil pores. Disaggregation and migration of palygorskite from the surface soil during rainfall and/or irrigation may have an effect on the degree of erosion as well. Palycretes (duripans in which the cementing material is dominantly composed of palygorskite) can be formed in some landscapes. Where palycretes occur close to the surface, plant growth is severely impeded. Palycretes also reduce water permeability of the soils, creating water-logged conditions that necessitate drainage installation. In situ immobilization (or fixation) of metals can be defined as a reduction of the metal concentration in the soil solution by adding an amendment to the soil, leaving the soil porous structure intact. Palygorskite appeared as an effective amendment to immobilize metals in contaminated soils.Although some progress has been made recently in understanding the effects of palygorskite on chemical and physico-chemical properties of soils, much research remains to be done. Performing some additional studies on disaggregation potential and migration ability of palygorskite under conditions close to those in the field is strongly desirable. Scanning electron microscopy observations on possible changes in aggregation of palygorskite in soils following intensive irrigation might be useful. Studies of the rheological behaviour of soil clays with different mineralogical composition, and palygorskite-containing soil clays in particular, are strongly encouraged. There is a need as well to study interactions of various contaminants (both organic and inorganic) with palygorskite-containing soils.