Kronenberg Henry M
Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Ann N Y Acad Sci. 2006 Apr;1068:1-13. doi: 10.1196/annals.1346.002.
Parathyroid hormone-related protein (PTHrP) participates in the regulation of endochondral bone development. After the cartilage mold is established in fetal life, perichondrial cells and chondrocytes at the ends of the mold synthesize PTHrP. This ligand then acts on PTH/PTHrP receptors on chondrocytes. As chondrocytes go through a program of proliferation and then further differentiation into post-mitotic, hypertrophic chondrocytes, PTHrP action keeps chondrocytes proliferating and delays their further differentiation. Indian hedgehog (Ihh) is synthesized by chondrocytes that have just stopped proliferating and is required for synthesis of PTHrP. The feedback loop between PTHrP and Ihh serves to regulate the pace of chondrocyte differentiation and the sites at which perichondrial cells first differentiate into osteoblasts. Activation of the PTH/PTHrP receptor leads to stimulation of both Gs and Gq family heterotrimeric G proteins. Genetic analyses demonstrate that Gs activation mediates the action of PTHrP to keep chondrocytes proliferating, while Gq activation opposes this action. Downstream from Gs activation, synthesis of the cyclin-cdk inhibitor, p57, is suppressed, thereby increasing the pool of proliferating chondrocytes. PTHrP's actions to delay chondrocyte differentiation are mediated by the phosphorylation of the transcription factor, SOX9, and by suppression of synthesis of mRNA encoding the transcription factor, Runx2. These pathways and undoubtedly others cooperate to regulate the pace of differentiation of growth plate chondrocytes in response to PTHrP.
甲状旁腺激素相关蛋白（PTHrP）参与软骨内骨发育的调节。在胎儿期软骨模板形成后，模板末端的软骨膜细胞和软骨细胞合成PTHrP。然后这种配体作用于软骨细胞上的甲状旁腺激素/甲状旁腺激素相关蛋白受体。随着软骨细胞经历增殖过程，然后进一步分化为有丝分裂后的肥大软骨细胞，PTHrP的作用使软骨细胞持续增殖并延迟其进一步分化。印度刺猬因子（Ihh）由刚停止增殖的软骨细胞合成，是PTHrP合成所必需的。PTHrP与Ihh之间的反馈环用于调节软骨细胞分化的速度以及软骨膜细胞首次分化为成骨细胞的部位。甲状旁腺激素/甲状旁腺激素相关蛋白受体的激活会导致Gs和Gq家族异源三聚体G蛋白的刺激。遗传分析表明，Gs激活介导PTHrP使软骨细胞增殖的作用，而Gq激活则对抗这种作用。在Gs激活的下游，细胞周期蛋白 - cdk抑制剂p57的合成受到抑制，从而增加增殖软骨细胞的数量。PTHrP延迟软骨细胞分化的作用是由转录因子SOX9的磷酸化以及编码转录因子Runx2的mRNA合成的抑制介导的。这些途径以及无疑其他途径共同协作，以响应PTHrP调节生长板软骨细胞的分化速度。
