Parathyroid Hormone (PTH)/PTH-related Peptide Type 1 Receptor (PPR) Signaling in Osteocytes Regulates Anabolic and Catabolic Skeletal Responses to PTH
Parathyroid Hormone (PTH)/PTH-related Peptide Type 1 Receptor (PPR) Signaling in Osteocytes Regulates Anabolic and Catabolic Skeletal Responses to PTH
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DOI：
10.1074/jbc.m112.441360
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发表时间：
2013-07-12
影响因子：
4.8
通讯作者：
Pajevic, Paola Divieti
中科院分区：
文献类型：
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作者：
Saini, Vaibhav;Marengi, Dean A.;Pajevic, Paola Divieti
甲状旁腺激素（PTH）是美国食品和药物管理局唯一批准用于治疗骨质疏松症的合成代谢药物；然而，骨中PTH作用的细胞靶点仍然存在争议。甲状旁腺激素通过结合甲状旁腺激素/甲状旁腺激素相关肽（PTHrP） 1型受体（PPR）调节骨转换，PPR是一种在骨和肾脏中高度表达的g蛋白偶联受体。成骨中最丰富的细胞骨细胞也表达PPR。然而，骨细胞中PPR信号的生理相关性仍有待阐明。为了实现这一目标，我们产生了骨细胞中PPR缺失的小鼠（Ocy-PPRKO）。对这些小鼠的骨骼分析显示，骨矿物质密度、骨小梁和骨皮质参数显著增加。这些动物的成骨细胞活性降低，胶原I型α 1 mRNA和nf - κ B配体受体激活因子（RANKL）表达降低。重要的是，当接受合成代谢或分解代谢甲状旁腺激素治疗时，Ocy-PPRKO动物表现出迟钝的骨骼反应。与对照组相比，PTH未能抑制Ocy-PPRKO动物的SOST/Sclerostin或诱导RANKL表达。在体外实验中，给药甲状旁腺激素后，Ocy-PPRKO的破骨细胞形成明显受损，表明骨细胞通过ppr介导的机制控制破骨细胞的形成。综上所述，这些数据表明骨细胞中的PPR信号是骨重塑所必需的，骨细胞中的受体信号是骨骼合成代谢和分解代谢反应所必需的。
Parathyroid hormone (PTH) is the only Food and Drug Administration-approved anabolic agent to treat osteoporosis; however, the cellular targets of PTH action in bone remain controversial. PTH modulates bone turnover by binding to the PTH/PTH-related peptide (PTHrP) type 1 receptor (PPR), a G-protein-coupled receptor highly expressed in bone and kidneys. Osteocytes, the most abundant cells in adult bone, also express PPR. However, the physiological relevance of PPR signaling in osteocytes remains to be elucidated. Toward this goal, we generated mice with PPR deletion in osteocytes (Ocy-PPRKO). Skeletal analysis of these mice revealed a significant increase in bone mineral density and trabecular and cortical bone parameters. Osteoblast activities were reduced in these animals, as demonstrated by decreased collagen type I alpha 1 mRNA and receptor activator of NF-kappa B ligand (RANKL) expression. Importantly, when subjected to an anabolic or catabolic PTH regimen, Ocy-PPRKO animals demonstrated blunted skeletal responses. PTH failed to suppress SOST/Sclerostin or induce RANKL expression in Ocy-PPRKO animals compared with controls. In vitro, osteoclastogenesis was significantly impaired in Ocy-PPRKO upon PTH administration, indicating that osteocytes control osteoclast formation through a PPR-mediated mechanism. Taken together, these data indicate that PPR signaling in osteocytes is required for bone remodeling, and receptor signaling in osteocytes is needed for anabolic and catabolic skeletal responses.