降钙素基因相关肽可刺激基质细胞成骨分化，并抑制 RANKL 诱导的 NF-κB 活化、破骨细胞生成和骨质吸收。
Calcitonin-gene-related peptide stimulates stromal cell osteogenic differentiation and inhibits RANKL induced NF-kappaB activation, osteoclastogenesis and bone resorption.
机构信息
Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
出版信息
Bone. 2010 May;46(5):1369-79. doi: 10.1016/j.bone.2009.11.029. Epub 2009 Dec 2.
Previously we observed that capsaicin treatment in rats inhibited sensory neuropeptide signaling, with a concurrent reduction in trabecular bone formation and bone volume, and an increase in osteoclast numbers and bone resorption. Calcitonin-gene-related peptide (CGRP) is a neuropeptide richly distributed in sensory neurons innervating the skeleton and we postulated that CGRP signaling regulates bone integrity. In this study we examined CGRP effects on stromal and bone cell differentiation and activity in vitro. CGRP receptors were detected by immunocytochemical staining and real time PCR assays in mouse bone marrow stromal cells (BMSCs) and bone marrow macrophages (BMMs). CGRP effects on BMSC proliferation and osteoblastic differentiation were studied using BrdU incorporation, PCR products, alkaline phosphatase (ALP) activity, and mineralization assays. CGRP effects on BMM osteoclastic differentiation and activity were determined by quantifying tartrate-resistant acid phosphatase positive (TRAP(+)) multinucleated cells, pit erosion area, mRNA levels of TRAP and cathepsin K, and nuclear factor-kappaB (NF-kappaB) nuclear localization. BMSCs, osteoblasts, BMMs, and osteoclasts all expressed CGRP receptors. CGRP (10(-10)-10(-8) M) stimulated BMSC proliferation, up-regulated the expression of osteoblastic genes, and increased ALP activity and mineralization in the BMSCs. In BMM cultures CGRP (10(-8) M) inhibited receptor activator of NF-kappaB ligand (RANKL) activation of NF-kappaB. CGRP also down-regulated osteoclastic genes like TRAP and cathepsin K, decreased the numbers of TRAP(+) cells, and inhibited bone resorption activity in RANKL stimulated BMMs. These results suggest that CGRP signaling maintains bone mass both by directly stimulating stromal cell osteoblastic differentiation and by inhibiting RANKL induced NF-kappaB activation, osteoclastogenesis, and bone resorption.
先前我们观察到辣椒素处理大鼠可抑制感觉神经肽信号，同时减少小梁骨形成和骨量，增加破骨细胞数量和骨吸收。降钙素基因相关肽（CGRP）是一种丰富分布于感觉神经元的神经肽，这些神经元支配骨骼，我们推测 CGRP 信号调节骨完整性。在这项研究中，我们检查了 CGRP 对体外基质和成骨细胞分化和活性的影响。通过免疫细胞化学染色和实时 PCR 检测在小鼠骨髓基质细胞（BMSCs）和骨髓巨噬细胞（BMMs）中检测 CGRP 受体。通过 BrdU 掺入、PCR 产物、碱性磷酸酶（ALP）活性和矿化测定研究 CGRP 对 BMSC 增殖和成骨细胞分化的影响。通过定量抗酒石酸酸性磷酸酶阳性（TRAP(+)）多核细胞、侵蚀面积、TRAP 和组织蛋白酶 K 的 mRNA 水平以及核因子-kappaB（NF-kappaB）核定位来确定 CGRP 对 BMM 破骨细胞分化和活性的影响。BMSCs、成骨细胞、BMMs 和破骨细胞均表达 CGRP 受体。CGRP（10(-10)-10(-8) M）刺激 BMSC 增殖，上调成骨细胞基因的表达，并增加 BMSCs 中的 ALP 活性和矿化。在 BMM 培养物中，CGRP（10(-8) M）抑制核因子-kappaB 配体（RANKL）激活 NF-kappaB。CGRP 还下调 TRAP 和组织蛋白酶 K 等破骨细胞基因，减少 TRAP(+)细胞数量，并抑制 RANKL 刺激的 BMM 中的骨吸收活性。这些结果表明，CGRP 信号通过直接刺激基质细胞成骨细胞分化和抑制 RANKL 诱导的 NF-kappaB 激活、破骨细胞生成和骨吸收来维持骨量。
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