The role and mechanism of parathyroid hormone in promoting bone formation

doi:10.3969/j.issn.2095-4344.2015.15.021

Abstract

Abstract:

BACKGROUND: Osteoporosis is characterized by low bone mineral density and/or poor bone microarchitecture leading to an increased risk of fractures. Oral manifestations can be frequently discovered in osteoporosis patients. Osteoporosis therapies have mostly relied on antiresorptive drugs. Parathyroid hormone plays a significant role in osteogenesis and calcium deposition. Intermittent exposure to parathyroid hormone has been widely proved to lead to a net increase in bone formation.
OBJECTIVE: To discuss the possibly cellular and molecular mechanism of parathyroid hormone in strengthening the bone mineral density and regulating bone formation.
METHODS: An online search of CNKI and Medline databases was performed for relevant articles using keywords of “parathyroid hormone; osteoporosis; osteoblast; osteogenesis” in Chinese and English, respectively. Relevant articles were summarized from three aspects: effects of parathyroid hormone on differentiation and proliferation of osteoblasts, effects of parathyroid hormone on osteoblast apoptosis, and the relationship of parathyroid hormone with Wnt/beta-catenin pathway and other cytokines. According to inclusion criteria, 41 articles were retained at last.
RESULTS AND CONCLUSION：Parathyroid hormone exerts an effect on parathyroid hormone type I receptor, triggering a classic G protein signaling pathway. Parathyroid hormone mainly works through protein kinase A signaling pathway, adjusting its downstream c-reactive protein. Intermittent use of parathyroid hormone can increase osteoblast proliferation, increase osteoblast runx2 and osteocalcin at mRNA and protein levels, inhibit osteoblast apoptosis by against oxidative stress, so as to promote osteogenesis.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

全文链接：

Key words: Thyroid Hormones, Osteoblasts, Cytokines

CLC Number:

R318

Wang Min-jiao, Si Jia-wen, Shen Guo-fang. The role and mechanism of parathyroid hormone in promoting bone formation[J]. Chinese Journal of Tissue Engineering Research, 2015, 19(15): 2405-2409.

Figures/Tables 1

2.1 骨质疏松与甲状旁腺激素甲状旁腺激素是由84个氨基酸组成的钙调节激素，由甲状旁腺释放，主要作用于肾脏和骨组织。其活性片段(甲状旁腺激素1-34)，亦具有甲状旁腺激素相同的生理作用。甲状旁腺激素作为临床用药，间断使用促进骨质形成以及预防骨折的效果已经得到广泛证实。为评价人甲状旁腺素预防骨质疏松性骨折的安全性和有效性，加拿大骨质疏松临床指南委员会Cranney等检索了Medline、Embase、HTA、Current Contents和Cochrane对照临床试验注册数据库中自1966至2005年2月的相关随机对照研究，并进行了系统评价。共有12项随机、安慰剂或活性药物对照的临床研究被纳入分析，治疗时间均≥1年。结果显示，人甲状旁腺激素(1-34)显著增加了腰椎骨密度，轻度增加了股骨颈和全髋骨密度；人甲状旁腺激素(1-84)也显著增加了腰椎骨密度。对于有脊椎骨折史的绝经后妇女，人甲状旁腺激素(1-34)显著降低了再发生脊柱和非脊柱骨折的危险[7]。研究显示治疗20个月后停用甲状旁腺激素，骨折风险还在持续降低，并可维持50个月以上，中国SFDA批准甲状旁腺激素使用24个月，目前考虑其安全性与不良反应的因素，常用剂量为20 μg/d，一般使用时间不超过2年[8]。甲状旁腺激素造成的骨质变化时一个复杂的过程，它既能刺激成骨细胞调节的骨形成，亦可以刺激破骨细胞调节的骨吸收，间歇性的甲状旁腺激素注射已经被广泛的证实可以刺激骨质的形成[9-10]。Lindsay等[11]比较每日甲状旁腺激素间歇性给药的患者1个月前后的骨密度，发现给药后的骨密度明显增加。研究表明，间歇性的甲状旁腺激素给药主要作用于四肢骨中的骨小梁以及密质骨表面，少量作用于骨膜表面，通过刺激成骨细胞增殖，抑制成骨细胞凋亡，同时激活衬里细胞，从而促进骨质形成[12-13]。 2.2 作用机制甲状旁腺激素作用于甲状旁腺激素Ⅰ型受体(PPR)，PPR是一种在肾脏和骨组织中广泛分布的经典的Ⅱ型G蛋白偶联受体，该受体有7个跨膜区，触发经典的G蛋白信号通路，一种是蛋白激酶A 信号通路(protein kinase A pathway，PKA pathwav)，另一种是蛋白激酶C信号通路(protein kinase C pathway，PKC pathway)。甲状旁腺激素主要通过PKA信号通路调节其下游反应蛋白。cAMP-PKA信号通路被认为是传导甲状旁腺激素信号的主要路径[14]。Datta等[15]研究提示MAPKs/ERKs通路也参与PPR的骨形成调节，骨重建机制模式图见图2[15]。MAPKs/ERKs通路主要依赖于PKC通路[14]。"

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