Open AccessDefective postnatal endochondral bone development by chondrocyte-specific targeted expression of parathyroid hormone type 2 receptor
Author(s) -
Dibyendu K. Panda,
David Goltzman,
Andrew C. Karaplis
Publication year - 2012
Publication title -
endocrinology and metabolism/american journal of physiology: endocrinology and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.507
H-Index - 201
eISSN - 1522-1555
pISSN - 0193-1849
DOI - 10.1152/ajpendo.00254.2012
Subject(s) - chondrocyte , endochondral ossification , medicine , endocrinology , biology , parathyroid hormone , parathyroid hormone receptor , receptor , chondrogenesis , bone growth , parathyroid hormone related protein , ossification , immunostaining , sox9 , indian hedgehog , microbiology and biotechnology , genetically modified mouse , transgene , cartilage , anatomy , gene expression , immunohistochemistry , hormone receptor , calcium , stem cell , genetics , cancer , breast cancer , gene
The human parathyroid hormone type 2 receptor (PTH2R) is activated by PTH and by tuberoinfundibular peptide of 39 residues (TIP39), the latter likely acting as its natural ligand. Although the receptor is expressed at highest levels in the nervous system, we have observed that both PTH2R and TIP39 are expressed in the newborn mouse growth plate, with the receptor localizing in the resting zone and the ligand TIP39 localizing exclusively in prehypertrophic and hypertrophic chondrocytes. To address the role of PTH2R in postnatal skeletal growth and development, Col2a1-hPTH2R (PTH2R-Tg) transgenic mice were generated. The mice were viable and of nearly normal size at birth. Expression of the transgene in the growth plate was limited to chondrocytes. We found that chondrocyte proliferation was decreased, as determined by in vivo BrdU labeling of proliferating chondrocytes and CDK4 and p21 expression in the growth plate of Col2a1-hPTH2R transgenic mice. Similarly, the differentiation and maturation of chondrocytes was delayed, as characterized by decreased Sox9 expression and weaker immunostaining for the chondrocyte differentiation markers collagen type II and type X and proteoglycans. As well, there was altered expression of Gdf5, Wdr5, and β-catenin, factors implicated in chondrocyte maturation, proliferation, and differentiation.These effects impacted on the process of endochondral ossification, resulting in delayed formation of the secondary ossification center, and diminished trabecular bone volume. The findings substantiate a role for PTH2R signaling in postnatal growth plate development and subsequent bone mass acquisition.