Targeted overexpression of parathyroid hormone-related peptide in chondrocytes causes chondrodysplasia and delayed endochondral bone formation

被引:344
作者
Weir, EC
Philbrick, WM
Amling, M
Neff, LA
Baron, R
Broadus, AE
机构
[1] YALE UNIV,SCH MED,COMPARAT MED SECT,NEW HAVEN,CT 06520
[2] YALE UNIV,SCH MED,DEPT CELLULAR & MOL PHYSIOL,NEW HAVEN,CT 06520
[3] YALE UNIV,SCH MED,DEPT MED,NEW HAVEN,CT 06520
[4] YALE UNIV,SCH MED,DEPT ORTHOPAED,NEW HAVEN,CT 06520
[5] YALE UNIV,SCH MED,DEPT CELL BIOL,NEW HAVEN,CT 06520
关键词
developmental regulation; programmed differentiation; chondrodystrophy;
D O I
10.1073/pnas.93.19.10240
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Parathyroid hormone-related peptide (PTHrP) was initially identified as a product of malignant tumors that mediates paraneoplastic hypercalcemia. It is now known that the parathyroid hormone (PTH) and PTRrP genes are evolutionarily related and that the products of these two genes share a common receptor, the PTH/PTHrP receptor, PTHrP and the PTH/PTBrP receptor are widely expressed in both adult and fetal tissues, and recent gene-targeting and disruption experiments have implicated PTHrP as a developmental regulatory molecule. Apparent PTHrP functions include the regulation of endochondral bone development, of hair follicle formation, and of branching morphogenesis in the breast. Herein, we report that overexpression of PTHrP in chondrocytes using the mouse type II collagen promoter induces a novel form of chondrodysplasia characterized by short-limbed dwarfism and a delay in endochondral ossification. This features a delay in chondrocyte differentiation and in bone collar formation and is sufficiently marked that the mice are born with a cartilaginous endochondral skeleton. In addition to the delay, chondrocytes in the transgenic mice initially become hypertrophic at the periphery of the developing long bones rather than in the middle, leading to a seeming reversal in the pattern of chondrocyte differentiation and ossification. By 7 weeks, the delays in chondrocyte differentiation and ossification have largely corrected, leaving foreshortened and misshapen but histologically near-normal bones. These findings confirm a role for PTHrP as an inhibitor of the program of chondrocyte differentiation. PTHrP may function in this regard to maintain the stepwise differentiation of chondrocytes that initiates endochondral ossification in the midsection of endochondral bones early in development and that also permits linear growth at the growth plate later in development.
引用
收藏
页码:10240 / 10245
页数:6
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