Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA.
Biochem Biophys Res Commun. 2011 Oct 22;414(2):326-30. doi: 10.1016/j.bbrc.2011.09.060. Epub 2011 Sep 17.
BMPs (Bone morphogenetic proteins) such as BMP2 and BMP7 have been used about one decade as bone anabolic agents in orthopaedics. The BMP receptor ACVR1, which is a key receptor of BMP7, is expressed in bone. The pathological role of ACVR1 in humans has been reported: a point mutation in ACVR1 can cause fibrodysplasia ossificans progressiva (FOP) in which ectopic ossification occurs in skeletal muscles and deep connective tissues. The physiological function of ACVR1 in bone, however, is totally unknown. The purpose of this study is to investigate the endogenous role of ACVR1 in osteoblasts, one of the most dominant cell-types in bone. We generated Acvr1-null mice in an osteoblast-specific manner using an inducible Cre-loxP system. Surprisingly, we found that bone mass was increased in the Acvr1-null mice. Interestingly, canonical Wnt signaling was increased and expression levels of Wnt inhibitors Sost and Dkk1 were both suppressed in the null bones during the developmental stages. In addition, we confirmed that expression levels of both Sost and Dkk1 were upregulated by BMP7 dose-dependently in vitro. These results suggest that the Acvr1-deficiency can increase bone mass by activating Wnt signaling in which both Sost and Dkk1 expression levels are diminished. This study leads to a new concept of the BMP7-ACVR1-SOST/DKK1 axis in osteoblasts, in which BMP7 signaling through ACVR1 can reduce Wnt signaling via SOST/DKK1 and then inhibits osteogenesis. Although this concept is beyond the current known function of BMP7, it can explain the varied outcomes of BMP7 treatment. We believe BMP signaling can exhibit multifaceted effects by context and cell type.
骨形态发生蛋白（Bone morphogenetic proteins，BMPs）如 BMP2 和 BMP7 已在骨科中作为骨合成代谢药物使用约十年。BMP7 的关键受体 BMP 受体 ACVR1 在骨中表达。ACVR1 在人类中的病理作用已有报道：ACVR1 中的点突变可导致纤维发育不良性骨化性进展（fibrodysplasia ossificans progressiva，FOP），其中异位骨化发生在骨骼肌和深部结缔组织中。然而，ACVR1 在骨中的生理功能尚完全未知。本研究的目的是研究 ACVR1 在成骨细胞中的内源性作用，成骨细胞是骨中最主要的细胞类型之一。我们使用诱导型 Cre-loxP 系统以成骨细胞特异性方式生成 Acvr1 敲除小鼠。令人惊讶的是，我们发现 Acvr1 敲除小鼠的骨量增加。有趣的是，在发育阶段，空骨中的经典 Wnt 信号增加，Wnt 抑制剂 Sost 和 Dkk1 的表达水平均受到抑制。此外，我们证实 Sost 和 Dkk1 的表达水平均可被 BMP7 体外剂量依赖性地上调。这些结果表明，Acvr1 缺失可通过激活 Wnt 信号增加骨量，其中 Sost 和 Dkk1 的表达水平均降低。本研究提出了 BMP7-ACVR1-SOST/DKK1 轴在成骨细胞中的新概念，其中 BMP7 信号通过 ACVR1 可通过 SOST/DKK1 减少 Wnt 信号，从而抑制成骨作用。尽管这一概念超出了 BMP7 目前已知的功能，但它可以解释 BMP7 治疗的不同结果。我们相信 BMP 信号可以通过上下文和细胞类型表现出多方面的作用。
