Amling M, Neff L, Tanaka S, Inoue D, Kuida K, Weir E, Philbrick W M, Broadus A E, Baron R
Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
J Cell Biol. 1997 Jan 13;136(1):205-13. doi: 10.1083/jcb.136.1.205.
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.
甲状旁腺激素相关肽（PTHrP）似乎在骨骼发育中起主要作用。在小鼠中靶向破坏PTHrP基因会导致骨骼发育异常，软骨细胞成熟加速（阿米祖卡，N.，H. 沃肖斯基，J.E. 亨德森，D. 戈尔茨曼，和A.C. 卡拉普利斯。1994。《细胞生物学杂志》。126:1611 - 1623；卡拉普利斯，A.C.，A. 卢兹，J. 格洛瓦茨基，R.T. 布朗森，V.L.J. 蒂布勒维茨，H.M. 克朗enberg，和R.C. 马利根。1994。《基因与发育》。8: 277 - 289）。在詹森型人类干骺端软骨发育不良中发现了一种组成型激活的突变型PTH/PTHrP受体，该疾病的特征是骨骼成熟延迟（斯基帕尼，E.，K. 克鲁泽，和H. 于普纳。1995。《科学》（华盛顿特区）。268:98 - 100）。然而，PTHrP影响这一发育程序的分子机制仍知之甚少。我们在此报告，PTHrP在体外和体内均可增加生长板软骨细胞中Bcl - 2的表达，Bcl - 2是一种在多种细胞类型中控制程序性细胞死亡的蛋白质，导致软骨细胞向肥大和凋亡性细胞死亡的成熟延迟。因此，在转基因小鼠中，在胶原蛋白II启动子控制下PTHrP的过表达导致骨骼发育明显延迟。正如从这些结果所预期的那样，编码Bcl - 2的基因缺失导致软骨细胞成熟加速和长骨缩短。因此，Bcl - 2在控制软骨细胞成熟和骨骼发育的途径中位于PTHrP的下游。
