Roles of bone morphogenetic protein type I receptors and smad proteins in osteoblast and chondroblast differentiation

The biological effects of type I serine/threonine kinase receptors and Smad proteins were examined using an adenovirus-based vector system. Constituti vely active forms of bone morphogenetic protein (BMP) type I receptors (BMP R-IA and BMPR-IB; BMPR-I group) and those of activin receptor-like kinase ( ALK)-1 and ALK-2 (ALK-1 group) induced alkaline phosphatase activity in C2C 12 cells. Receptor-regulated Smads (R-Smads) that act in the BMP pathways, such as Smad1 and Smad5, also induced the alkaline phosphatase activity in C2C12 cells. BMP-6 dramatically enhanced alkaline phosphatase activity indu ced by Smad1 or Smad5, probably because of the nuclear translocation of R-S mads triggered by the ligand. Inhibitory Smads, i.e., Smad6 and Smad7, repr essed the alkaline phosphatase activity induced by BMP-6 or the type I rece ptors. Chondrogenic differentiation of ATDC5 cells was induced by the recep tors of the BMPR-I group but not by those of the ALK-1 group. However, kina se-inactive forms of the receptors of the ALK-1 and BMPR-I groups blocked c hondrogenic differentiation. Although R-Smads failed to induce cartilage no dule formation, inhibitory Smads blocked it. Osteoblast differentiation ind uced by BMPs is thus mediated mainly via the Smad-signaling pathway, wherea s chondrogenic differentiation may be transmitted by Smad-dependent and ind ependent pathways.