Division of Endocrinology, Department of Medicine and Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
Am J Physiol Endocrinol Metab. 2012 Dec 15;303(12):E1489-501. doi: 10.1152/ajpendo.00254.2012. Epub 2012 Oct 23.
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.
人类甲状旁腺激素 2 型受体 (PTH2R) 可被甲状旁腺激素和 39 个残基的脑垂体中间茎多肽 (TIP39) 激活，后者可能作为其天然配体发挥作用。尽管该受体在神经系统中表达水平最高，但我们观察到 PTH2R 和 TIP39 均在新生小鼠生长板中表达，受体定位于静止区，配体 TIP39 仅定位于肥大前和成骨细胞。为了研究 PTH2R 在出生后骨骼生长和发育中的作用，我们生成了 Col2a1-hPTH2R（PTH2R-Tg）转基因小鼠。这些小鼠在出生时具有活力且体型几乎正常。转基因在生长板中的表达仅限于软骨细胞。我们发现，通过体内 BrdU 标记增殖的软骨细胞和生长板中 CDK4 和 p21 的表达，软骨细胞增殖减少。同样，软骨细胞的分化和成熟也被延迟，表现为 Sox9 表达减少，以及软骨细胞分化标志物 II 型胶原和 X 型胶原和蛋白聚糖的免疫染色减弱。此外，Gdf5、Wdr5 和 β-连环蛋白的表达也发生改变，这些因子参与软骨细胞的成熟、增殖和分化。这些影响影响了软骨内化骨的过程，导致次生骨化中心形成延迟，小梁骨体积减少。这些发现证实了 PTH2R 信号在出生后生长板发育和随后骨量获得中的作用。
