Adult bone structural integrity is maintained by remodeling via the coupling of osteoclastic bone resorption and osteoblastic bone formation. Osteocytes or osteoblasts express receptor activator of nuclear factor κ-B ligand (Rankl) or osteoprotegerin (Opg) to promote or inhibit osteoclastogenesis, respectively. Bone morphogenetic protein (BMP) is a potent bone inducer, but its major role in adult bone is to induce osteocytes to upregulate sclerostin (Sost) and increase the Rankl/Opg expression ratio, resulting in promotion of osteoclastogenesis. However, the precise effect of BMP-target gene(s) in osteoblasts on the Rankl/Opg expression ratio remains unclear. In the present study, we identified atonal homolog 8 (Atoh8), which is directly upregulated by the BMP-Smad1 axis in osteoblasts. In vivo, Atoh8 was detected in osteoblasts but not osteocytes in adult mice. Although global Atoh8-knockout mice showed only a mild phenotype in the neonate skeleton, the bone volume was decreased and osteoclasts were increased in the adult phase. Atoh8-null marrow stroma cells were more potent than wild-type cells in inducing osteoclastogenesis in marrow cells. Atoh8 loss in osteoblasts increased Runx2 expression and the Rankl/Opg expression ratio, while Runx2 knockdown normalized the Rankl/Opg expression ratio. Moreover, Atoh8 formed a protein complex with Runx2 to inhibit Runx2 transcriptional activity and decrease the Rankl/Opg expression ratio. These results suggest that bone remodeling is regulated elaborately by BMP signaling; while BMP primarily promotes bone resorption, it simultaneously induces Atoh8 to inhibit Runx2 and reduce the Rankl/Opg expression ratio in osteoblasts, suppressing osteoclastogenesis and preventing excessive BMP-mediated bone resorption.

通过破骨细胞骨吸收和成骨细胞骨形成的耦合重塑来维持成人骨骼结构的完整性。骨细胞或成骨细胞表达核因子 κ-B 配体 (Rankl) 或骨保护素 (Opg) 的受体激活剂，以分别促进或抑制破骨细胞生成。骨形态发生蛋白 (BMP) 是一种有效的骨诱导剂，但其在成人骨骼中的主要作用是诱导骨细胞上调硬化蛋白 (Sost) 并增加 Rankl/Opg 表达比，从而促进破骨细胞生成。然而，成骨细胞中 BMP 靶基因对 Rankl/Opg 表达比的确切影响仍不清楚。在本研究中，我们确定了无调同系物 8 ( Atoh8)，其在成骨细胞中被 BMP-Smad1 轴直接上调。在体内，Atoh8 在成骨细胞中检测到，但在成年小鼠的骨细胞中未检测到。虽然全局 Atoh8 敲除小鼠在新生骨骼中仅显示出轻微的表型，但在成年期骨量减少并且破骨细胞增加。Atoh8-null 骨髓基质细胞在诱导骨髓细胞破骨细胞生成方面比野生型细胞更有效。成骨细胞中 Atoh8 的缺失增加了 Runx2 表达和 Rank1/Opg 表达比，而 Runx2 敲低使 Rank1/Opg 表达比正常化。此外，Atoh8 与 Runx2 形成蛋白质复合物以抑制 Runx2 转录活性并降低 Rank1/Opg 表达比。这些结果表明，骨重塑受 BMP 信号传导的精细调节；而 BMP 主要促进骨吸收，