Growth factors play important roles in the control of osteoblast (bone deposition) function through complex cellular and molecular mechanisms of action. The most prominent factors are those that are produced locally by osteoblasts and are present in the bone matrix. They include IGFs, fibroblast growth factors (FGFs), TGF- s, and bone morphogenetic proteins. Some of the signaling mechanisms of these factors have been identified in osteoblastic cells.

Insulin-like growth factors
IGFs are produced by osteoblasts and act through their receptors to activate both proliferation and differentiation. In vivo, IGF-I stimulates bone formation by acting on osteoblast recruitment and function. In vitro, IGF-I increases collagen type expression and synthesis and promotes osteoblast survival. The actions of IGFs are largely controlled by IGF binding proteins (IGFBPs) which are produced by osteoblasts and present in the bone matrix, and are regulated by local agents and specific proteases. Both IGFs and IGFBPs are controlled by 1,25-dihydroxyvitamin D, oestrogens, and PTH, suggesting that these factors are important local regulators of bone formation.

Transforming growth factor
TGF- is produced in latent forms by osteoblasts. Latent TGF- is stored in the bone matrix in association with latent TGF- binding protein (LTBP) and the latent complex can be released into mature biologically active TGF- by the action of plasmin and low pH produced by osteoclast during resorption. The biological activity of TGF- can also be controlled by interactions with the small proteoglycans decorin and beta glycan. In vivo, TGF- markedly stimulates bone formation in rats. In vitro, TGF- increases the proliferation of normal osteoblastic cells and stimulates the expression and production of bone matrix proteins such as type I collagen and osteopontin. In addition, TGF- reduces the rate of matrix degradation by acting on collagenase and metalloprotease enzymatic activities. TGF- also exerts anti-apoptotic effects on osteoblasts, which could complement its anabolic effects on bone formation. Since TGF- released from the matrix during resorption may stimulate osteoblast recruitment, this factor may serve as a coupling agent linking resorption to the subsequent formation during the bone remodeling cycle. TGF- has an inhibitory effect on bone resorption. The local injection of TGF-to ovariectomized rats reduces bone hyperresorption. In mice marrow cultures, TGF- decreases osteoclastic differentiation through a direct action on hematopoietic precursor cell proliferation. Another mechanism inducing the inhibition of osteo-clast differentiation could be to reduce RANK-L and to increase OPG expression by stromal/osteoblastic cells. Furthermore, TGF- increases osteoclast apoptosis. The synthesis of TGF- by osteoblasts is increased by estradiol and it could be one of the mediators of the inhibitory effect of estradiol on bone resorption.

Fibroblast growth factors
FGFs are essential molecules for the regulation of bone formation. The biological activity of FGFs depend on binding to and activation of high affinity FGF receptors (FGFRs). FGFR mutations engender multiple abnormalities in skeletal development, which emphasizes the importance of FGFR signaling in the control of skeletal formation. In the postnatal life, FGFs have important direct and indirect effects on the recruitment, differentiation, and survival of osteoblasts. In vivo, low dose FGF-2 stimulates endosteal bone formation in normal and osteopenic animals. In vitro, FGF-1 and FGF-2 stimulate osteoblastic cell proliferation, inhibit ALP and type 1 collagen expression, and modulates osteocalcin expression, whereas FGF-2 treatment increases osteocalcin synthesis and matrix mineralisation in marrow stromal cells or human calvaria cells in long-term cultures, showing that FGF-2 effects are dependent upon the stage of osteoblast maturation. Part of the anabolic effects of FGFs may be mediated by stimulation of TGF- , IGF-I, IGF-II, and IGFBPs. Additionally, FGF-2 promotes osteoblast survival. This factor is therefore likely to be important in the local control of bone formation