The local regulation of osteoblast differentiation and function is not well understood. There is close coupling of bone resorption and bone formation both temporally and spatially but the signals that link these two processes are not identified. Many growth factors and cytokines are expressed in bone and have profound effects on osteoblast differentiation and function in vitro and in vivo; however, their relative importance and sequence of action in normal bone physiology are also unknown. Some factors are potent proliferative reagents for osteoblast precursors while others appear more important for lineage commitment and differentiation. It appears to be a regulatory system with high levels of redundancy and overlapping function. Many of these factors are made by osteoblasts and are present in significant amounts sequestered in bone matrix and so have the potential to be released by osteoclasts during bone resorption. However, while gaining an understanding of physiology is very important, our knowledge is sufficient to identify a large number of specific factors with proven and unproven therapeutic potential.19
Among the strongly proliferative factors are fibroblast growth factor 1 and 2 (FGF-1 and -2), transforming growth factor b (TGFb) and platelet-derived growth factor (PDGF). In vitro, these factors potently promote osteoblast precursor proliferation but inhibit osteoblast differentiation. In vivo, they promote new bone formation but bone formed is disorganized woven bone and mineralization can be inhibited. PDGF in particular may have an important role in fracture repair where rapid formation of a fracture callus is required.20 The systemic use of these factors is limited by their pleiotropic proliferative effects on other tissues.
IGF-1 and -2 are weaker mitogens for osteoblast precursors and also promote initial differentiation. Their physiologic role is in part to mediate the anabolic actions of growth hormone. They have modest anabolic effects on bone when given systemically, though dosing tends to be limited by agonist actions on the insulin receptor at higher circulating concentrations.
In contrast, bone morphogenetic proteins (BMPs) have weak proliferative effects in vitro but are potent differentiation agents for osteoblast precursors and can induce the formation of ectopic bone in vivo. BMP2 and BMP7 are used clinically to promote fracture repair and closure of bone defects. BMPs act physiologically as autocrine and paracrine factors that promote osteoblast lineage commitment and regulate osteoblast differentiation.19
Wnt proteins signal through b-catenin and are important in bone metabolism, as absence of Wnt signaling induces osteopenia and constitutive activation of the Wnt pathway produces a high-bone-mass phenotype in human patients. Wnts appear to have an important role in osteoblast lineage commitment and in providing autocrine signals vital for full osteoblast differentiation. The human high-bone-mass phenotype in particular has provided strong validation for the concept that a Wnt pathway agonist could have bone anabolic actions.21
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