Constitutively active parathyroid hormone receptor signaling in cells in osteoblastic lineage suppresses mechanical unloading-induced bone resorption
Constitutively active parathyroid hormone receptor signaling in cells in osteoblastic lineage suppresses mechanical unloading-induced bone resorption
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DOI：
10.1074/jbc.m610782200
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发表时间：
2007-08-31
影响因子：
4.8
通讯作者：
Noda, Masaki
中科院分区：
文献类型：
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作者：
Ono, Noriaki;Nakashima, Kazuhisa;Noda, Masaki
多种信号通路参与骨重建的调节，调节过程中病理性负平衡导致骨质疏松。然而，信号通路的相互作用，全面一致，以保持骨量还没有完全理解。我们使用转基因小鼠研究了成骨细胞中甲状旁腺激素受体（PTH/PTHrP受体）信号转导在卸载诱导的骨丢失中的作用。通过尾部悬吊使后肢卸载降低了野生型小鼠的骨量。与此相反，组成性激活PTH/PTHrP受体（caPPR），其表达受成骨细胞特异性Col 1a 1启动子（Col 1a 1-caPPR）调控的信号传导，抑制了这些转基因小鼠中卸载诱导的骨量减少。在Col 1a 1-caPPR转基因（Tg）小鼠中，后肢卸载抑制体内骨形成参数和体外矿化结节形成，与野生型小鼠中观察到的相似。此外，血清骨钙素水平和I型胶原，Runx 2和Osterix在骨中的mRNA表达水平被抑制卸载在野生型小鼠和Tg小鼠。然而，与卸载诱导的野生型小鼠骨吸收参数增强相反，Col 1a 1-capPPR信号抑制，而不是增强，破骨细胞数量和破骨细胞表面以及尿脱氧吡啶啉排泄卸载后。Col 1a 1-caPPR信号传导还抑制了卸载后骨中RANK和c-fms的mRNA表达水平。虽然M-CSF和单核细胞趋化蛋白1（MCP-1）的mRNA水平在对照Tg小鼠增强，这些水平被抑制在卸载Tg小鼠。这些结果表明成骨细胞中PTH/PTHrP受体信号传导的组成性激活特异性地通过调节骨细胞活性来抑制卸载诱导的骨丢失。
Multiple signaling pathways participate in the regulation of bone remodeling, and pathological negative balance in the regulation results in osteoporosis. However, interactions of signaling pathways that act comprehensively in concert to maintain bone mass are not fully understood. We investigated roles of parathyroid hormone receptor ( PTH/PTHrP receptor) signaling in osteoblasts in unloading-induced bone loss using transgenic mice. Hind limb unloading by tail suspension reduced bone mass in wild-type mice. In contrast, signaling by constitutively active PTH/PTHrP receptor ( caPPR), whose expression was regulated by the osteoblast-specific Col1a1 promoter ( Col1a1-caPPR), suppressed unloading-induced reduction in bone mass in these transgenic mice. In Col1a1-caPPR transgenic ( Tg) mice, hind limb unloading suppressed bone formation parameters in vivo and mineralized nodule formation in vitro similarly to those observed in wild-type mice. In addition, serum osteocalcin levels and mRNA expression levels of type I collagen, Runx2 and Osterix in bone were suppressed by unloading in both wild-type mice and Tg mice. However, in contrast to unloading-induced enhancement of bone resorption parameters in wild-type mice, Col1a1-caPPR signaling suppressed, rather than enhanced, osteoclast number and osteoclast surface as well as urinary deoxypyridinoline excretion upon unloading. Col1a1-caPPR signaling also suppressed mRNA expression levels of RANK and c-fms in bone upon unloading. Although the M-CSF and monocyte chemoattractant protein 1 ( MCP-1) mRNA levels were enhanced in control Tg mice, these levels were suppressed in unloaded Tg mice. These results indicated that constitutive activation of PTH/PTHrP receptor signaling in osteoblastic cells suppresses unloading-induced bone loss specifically through the regulation of osteoclastic activity.