Extracellular regulation of transforming growth factor beta and bone morphogenetic protein signaling in bone.

Systemic and local factors regulate the activity of osteoblasts and osteoclasts during bone growth and remodeling by modulating a complex array of intracellular signaling events. Recent genetic evidence implicates extracellular fibrillin assemblies (microfibrils and elastic fibers) in imparting contextual specificity to endogenous transforming growth factor-beta and bone morphogenetic protein ligands in the forming and mature skeleton. The evidence is based on the characterization of the cellular and molecular mechanisms responsible for the unique bone manifestations that characterize mouse models of Marfan syndrome and congenital contractural arachnodactyly. Collectively, the studies indicate that fibrillin assemblies play a key role both in establishing morphogen gradients within the developing limbs and in restricting growth factors activity in remodeling bones. The latter finding is likely to improve the design of more effective therapeutic interventions in osteoporosis and of bioengineering formulations for the repair of bone fractures.