Defective postnatal endochondral bone development by chondrocyte-specific targeted expression of parathyroid hormone type 2 receptor

Abstract

Panda DK, Goltzman D, Karaplis AC. Defective postnatal endochondral bone development by chondrocyte-specific targeted expression of parathyroid hormone type 2 receptor. 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 ␤-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.

The Parathyroid Hormone Second Receptor PTH2R and its Ligand Tuberoinfundibular Peptide of 39 Residues TIP39 Regulate Intracellular Calcium and Influence Keratinocyte Differentiation

“…TIP39/PTH2R signaling also has been observed to inhibit the proliferation and alter differentiation of a rat chondrocyte cell line in vitro (Panda et al, 2009). Consistent with this, chondrocyte proliferation was decreased in transgenic mice engineered to overexpress human PTH2R using the Col2a1 promoter (Panda et al, 2012). …”

The Chinese Medicinal Formulation Guzhi Zengsheng Zhitongwan Modulates Chondrocyte Structure, Dynamics, and Metabolism by Controlling Multiple Functional Proteins

“…Dap, Phlpp2, and Sh3glb1 are important mediators involved in cell survival and death through regulating multiple signal transduction pathways [38–40]. Pth2, a ligand for the parathyroid hormone 2 receptor, plays a pivotal role in regulating chondrocyte proliferation and differentiation [41]. Akap8 is a member of the A-kinase anchoring protein family that is mainly expressed in the matrix of precartilage but not in fully differentiated cartilage [42].…”

Breakpoint mapping by whole genome sequencing identifiesPTH2Rgene disruption in a patient with midline craniosynostosis and a de novo balanced chromosomal rearrangement

“… 15 In a subsequent study, it was found that targeted expression of PTH2R in growth plate chondrocytes impaired endochondral ossification by decreasing proliferation while impairing differentiation of chondrocytes, which suggests that TIP39/PTH2R has a crucial role in the regulation of chondrocytic proliferation and differentiation. 16 Thus, it is likely that disruption of the PTH2R gene in our patient may have caused reduced expression of PTH2R or production of aberrant PTH2R, which led to decreased TIP29/PTH2R signalling and uncontrolled proliferation and differentiation of chondrocytes that in turn resulted in premature closure of sutures.…”

“…The IHH protein, which is expressed in prehypertrophic chondrocytes, is known to play a major role in endochondral bone formation by regulating proliferation and differentiation via the PTHrP controlled feedback loop. 16 The duplication of locus 2q35, which includes the IHH gene, causes increased IHH expression, which is likely to cause osteoblast proliferation and consecutive overgrowth that results in CRS. 17 IHH has also been shown to stimulate chondrocyte proliferation independently of PTHrP signalling, indicating a possible interaction between PTH2R and IHH in regulating chondrocyte proliferation.…”