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 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.
Amling
M
M
Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Neff
L
L
Tanaka
S
S
Inoue
D
D
Kuida
K
K
Weir
E
E
Philbrick
W M
WM
Broadus
A E
AE
Baron
R
R
D000818:Animals; D017209:Apoptosis; D001846:Bone Development; D002356:Cartilage / Q000737:chemistry / Q000254:growth & development* / Q000473:pathology; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics; D015870:Gene Expression; D006132:Growth Plate / Q000737:chemistry / Q000473:pathology; D006801:Humans; D006984:Hypertrophy; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009928:Organ Specificity; D044162:Parathyroid Hormone-Related Protein; D011401:Promoter Regions, Genetic / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction / Q000502:physiology*; D051028:bcl-2-Associated X Protein
C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D051028:bcl-2-Associated X Protein; D003094:Collagen