Department of Bone and Joint Disease, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.
Laboratory of Research Advancement, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.
J Bone Miner Res. 2018 Aug;33(8):1500-1512. doi: 10.1002/jbmr.3436. Epub 2018 May 11.
The osteoclast-derived collagen triple helix repeat containing 1 (CTHRC1) protein stimulates osteoblast differentiation, but the underlying mechanism remains unclear. Here, we identified Wnt-activated inhibitory factor 1 (WAIF1)/5T4 as a cell-surface protein binding CTHRC1. The WAIF1-encoding Trophoblast glycoprotein (Tpbg) gene, which is abundantly expressed in the brain and bone but not in other tissues, showed the same expression pattern as Cthrc1. Tpbg downregulation in marrow stromal cells reduced CTHRC1 binding and CTHRC1-stimulated alkaline phosphatase activity through PKCδ activation of MEK/ERK, suggesting a novel WAIF1/PKCδ/ERK pathway triggered by CTHRC1. Unexpectedly, osteoblast lineage-specific deletion of Tpbg downregulated Rankl expression in mouse bones and reduced both bone formation and resorption; importantly, it impaired bone mass recovery following RANKL-induced resorption, reproducing the phenotype of osteoclast-specific Cthrc1 deficiency. Thus, the binding of osteoclast-derived CTHRC1 to WAIF1 in stromal cells activates PKCδ-ERK osteoblastogenic signaling and serves as a key molecular link between bone resorption and formation during bone remodeling. © 2018 American Society for Bone and Mineral Research.
骨吸收细胞来源的三螺旋重复胶原 1（CTHRC1）蛋白刺激成骨细胞分化，但潜在机制尚不清楚。在这里，我们鉴定出 Wnt 激活抑制因子 1（WAIF1）/5T4 是一种与 CTHRC1 结合的细胞表面蛋白。WAIF1 编码的滋养层糖蛋白（Tpbg）基因在大脑和骨骼中大量表达，但在其他组织中不表达，其表达模式与 Cthrc1 相同。骨髓基质细胞中 Tpbg 的下调降低了 CTHRC1 的结合和 CTHRC1 刺激的碱性磷酸酶活性，这是通过 PKCδ 激活 MEK/ERK 实现的，提示存在一条由 CTHRC1 触发的新型 WAIF1/PKCδ/ERK 通路。出乎意料的是，成骨细胞谱系特异性的 Tpbg 缺失下调了小鼠骨骼中的 Rankl 表达，降低了骨形成和吸收；重要的是，它损害了 RANKL 诱导的吸收后骨量的恢复，重现了破骨细胞特异性 Cthrc1 缺乏的表型。因此，骨吸收细胞来源的 CTHRC1 与基质细胞中的 WAIF1 结合，激活 PKCδ-ERK 成骨细胞信号通路，并在骨重塑过程中充当骨吸收和形成之间的关键分子联系。
