Kamiya Nobuhiro, Ye Ling, Kobayashi Tatsuya, Lucas Donald J, Mochida Yoshiyuki, Yamauchi Mitsuo, Kronenberg Henry M, Feng Jian Q, Mishina Yuji
Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
J Bone Miner Res. 2008 Dec;23(12):2007-17. doi: 10.1359/jbmr.080809.
Bone morphogenetic proteins (BMPs) are known as ectopic bone inducers. The FDA approved BMPs (BMP2 and BMP7) for clinical use. However, direct effects of BMPs on endogenous bone metabolism are not yet well known. We conditionally disrupted BMP receptor type IA (BMPRIA) in osteoblasts during weanling and adult stages to show the impact of BMP signaling on endogenous bone modeling and remodeling. Cre recombination was detected in immature osteoblasts in the periosteum, osteoblasts, and osteocytes but not in chondrocytes and osteoclasts after tamoxifen administration. Bmpr1a conditional knockout mice (cKO) showed increased bone mass primarily in trabecular bone at P21 and 22 wk as determined by H&E staining. Vertebrae, tails, and ribs showed increased radiodensity at 22 wk, consistent with a significant increase in BMD. Both muCT and histomorphometry showed an increase in trabecular BV/TV and thickness of cKO adult bones, whereas osteoclast number, bone formation rate, and mineral apposition rate were decreased. Expression levels of bone formation markers (Runx2 and Bsp), resorption markers (Mmp9, Ctsk, and Tracp), and Rankl were decreased, and Opg was increased in adult bones, resulting in a reduction in the ratio of Rankl to osteoprotegerin (Opg). The reduction in osteoclastogenesis through the RANKL-OPG pathway was also observed in weanling stages and reproduced in newborn calvaria culture. These results suggest that Bmpr1a cKO increased endogenous bone mass primarily in trabecular bone with decreased osteoclastogenesis through the RANKL-OPG pathway. We conclude that BMPRIA signaling in osteoblasts affects both bone formation and resorption to reduce endogenous bone mass in vivo.
骨形态发生蛋白（BMPs）被称为异位骨诱导剂。美国食品药品监督管理局（FDA）已批准BMPs（BMP2和BMP7）用于临床。然而，BMPs对内源性骨代谢的直接影响尚不清楚。我们在断奶期和成年期有条件地破坏成骨细胞中的I型BMP受体（BMPRIA），以显示BMP信号传导对内源性骨建模和重塑的影响。给予他莫昔芬后，在骨膜中的未成熟成骨细胞、成骨细胞和骨细胞中检测到Cre重组，但在软骨细胞和破骨细胞中未检测到。通过苏木精和伊红（H&E）染色确定，Bmpr1a条件性敲除小鼠（cKO）在出生后21天和22周时主要在小梁骨中骨量增加。在22周时，椎骨、尾巴和肋骨的放射密度增加，与骨密度显著增加一致。微计算机断层扫描（muCT）和组织形态计量学均显示cKO成年骨的小梁骨体积分数（BV/TV）和厚度增加，而成骨细胞数量、骨形成率和矿物质沉积率降低。成年骨中骨形成标志物（Runx2和骨唾液酸蛋白（Bsp））、吸收标志物（基质金属蛋白酶9（Mmp9）、组织蛋白酶K（Ctsk）和抗酒石酸酸性磷酸酶（Tracp））以及核因子κB受体活化因子配体（Rankl）的表达水平降低，骨保护素（Opg）增加，导致Rankl与骨保护素（Opg）的比值降低。在断奶期也观察到通过RANKL-Opg途径破骨细胞生成减少，并在新生颅骨培养中重现。这些结果表明，Bmpr1a基因敲除主要通过RANKL-Opg途径减少破骨细胞生成，从而增加小梁骨中的内源性骨量。我们得出结论，成骨细胞中的BMPRIA信号传导影响骨形成和吸收，以减少体内的内源性骨量。
