title: Defective postnatal endochondral bone development by chondrocyte-specific targeted expression of parathyroid hormone type 2 receptor.
abstract: 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.
authors.affiliation: Division of Endocrinology, Department of Medicine and Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Dibyendu Kumar
authors.initials: DK
authors.lastname: Panda
authors.forename: David
authors.initials: D
authors.lastname: Goltzman
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Karaplis
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000378:metabolism; D001848:Bone Diseases, Developmental / Q000378:metabolism* / Q000473:pathology; D001842:Bone and Bones / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D049109:Cell Proliferation; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D006132:Growth Plate / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D010040:Otosclerosis / Q000378:metabolism / Q000473:pathology; D044183:Receptor, Parathyroid Hormone, Type 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D015415:Biomarkers; C499177:COL2A1 protein, human; D024043:Collagen Type II; D044183:Receptor, Parathyroid Hormone, Type 2; D011994:Recombinant Proteins; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D015689:Oncogene Protein p21(ras)