J. Cell Biol.
© The Rockefeller University Press
0021-9525/97/01/205/09 $2.00
Volume 136, Number 1, January 13, 1997 205-213

Bcl-2 Lies Downstream of Parathyroid Hormone-related Peptide in a Signaling Pathway That Regulates Chondrocyte Maturation during Skeletal Development

Michael Amling,^*§ Lynn Neff,^* Sakae Tanaka,^* Daisuke Inoue,^* Keisuke Kuida, Eleanor Weir,^¶ William M. Philbrick,^¶ Arthur E. Broadus,^¶** and Roland Baron^*

^* Department of Cell Biology,  Department of Orthopaedics, ^¶ Department of Internal Medicine, ^** Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, 06510; ^§ Department of Bone Pathology, Hamburg University School of Medicine, 20246 Hamburg, Germany; and  Tokyo Metropolitan Institute of Medical Science, Tokyo 113, Japan

Parathyroid hormone-related peptide (PTHrP) appears to play a major role in skeletal development. Targeted disruption of the PTHrP gene in mice causes skeletal dysplasia with accelerated chondrocyte maturation (Amizuka, N., H. Warshawsky, J.E. Henderson, D. Goltzman, and A.C. Karaplis. 1994. J. Cell Biol. 126:1611-1623; Karaplis, A.C., A. Luz, J. Glowacki, R.T. Bronson, V.L.J. Tybulewicz, H.M. Kronenberg, and R.C. Mulligan. 1994. Genes Dev. 8: 277-289). A constitutively active mutant PTH/PTHrP receptor has been found in Jansen-type human metaphyseal chondrodysplasia, a disease characterized by delayed skeletal maturation (Schipani, E., K. Kruse, and H. Jüppner. 1995. Science (Wash. DC). 268:98- 100). The molecular mechanisms by which PTHrP affects this developmental program remain, however, poorly understood. We report here that PTHrP increases the expression of Bcl-2, a protein that controls programmed cell death in several cell types, in growth plate chondrocytes both in vitro and in vivo, leading to delays in their maturation towards hypertrophy and apoptotic cell death. Consequently, overexpression of PTHrP under the control of the collagen II promoter in transgenic mice resulted in marked delays in skeletal development. As anticipated from these results, deletion of the gene encoding Bcl-2 leads to accelerated maturation of chondrocytes and shortening of long bones. Thus, Bcl-2 lies downstream of PTHrP in a pathway that controls chondrocyte maturation and skeletal development.

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