BCL-2 LIES DOWNSTREAM OF PARATHYROID HORMONE-RELATED PEPTIDE IN A SIGNALING PATHWAY THAT REGULATES CHONDROCYTE MATURATION DURING SKELETAL DEVELOPMENT

Parathyroid hormone-related peptide (PTHrP) appears to play a major ro le in skeletal development. Targeted disruption of the PTHrP gene in m ice causes skeletal dysplasia with accelerated chondrocyte maturation (Amizuka, N., H. Warshawsky, J.E. Henderson, D. Goltzman, and A.C. Kar aplis. 1994. J. Cell Biol. 126:1611-1623; Karaplis, A.C., A. Luz, J. G Iowacki, R.T. Bronson, V.L.J. Tybulewicz, H.M. Kronenberg, and R.C. Mu lligan. 1994. Genes Dev. 8: 277-289). A constitutively active mutant P TH/PTHrP receptor has been found in Jansen-type human metaphyseal chon drodysplasia, a disease characterized by delayed skeletal maturation ( Schipani, E., K. Kruse, and H. Juppner. 1995. Science (Wash. DC). 268: 98-100). The molecular mechanisms by which PTHrP affects this developm ental program remain, however, poorly understood. We report here that PTHrP increases the expression of Bcl-2, a protein that controls progr ammed cell death in several cell types, in growth plate chondrocytes b oth in vitro and in vivo, leading to delays in their maturation toward s hypertrophy and apoptotic cell death. Consequently, overexpression o f PTHrP under the control of the collagen II promoter in transgenic mi ce resulted in marked delays in skeletal development. As anticipated f rom these results, deletion of the gene encoding Bcl-2 leads to accele rated maturation of chondrocytes and shortening of long bones. Thus, B cl-2 lies downstream of PTHrP in a pathway that controls chondrocyte m aturation and skeletal development.