我们之前曾报道过，缺乏 Wnt 信号拮抗剂 Sfrp4 的小鼠中观察到的皮质骨变薄部分是由于骨膜附着受损所致。骨膜含有充当干细胞库的细胞，有助于皮质骨扩张、体内平衡和修复。然而，控制骨膜生态位内干细胞的局部或旁分泌因子仍然难以捉摸。组织蛋白酶 K (Ctsk) 与其他干细胞表面标记物一起标记骨膜干细胞 (PSC) 的一个子集，其具有自我更新能力和可诱导的多能性。 Sfrp4 在骨膜 Ctsk 谱系细胞中表达，Sfrp4 整体缺失会减少 PSC 池，损害其分化为成骨细胞和软骨细胞以及骨类器官形成的克隆多能性。 Ctsk 谱系 PSC 的批量 RNA 测序分析表明，Sfrp4 缺失会下调与骨骼发育、骨矿化的正向调节和伤口愈合相关的信号通路。支持这些发现的是，Sfrp4 缺失阻碍了骨膜对骨损伤的反应，并损害了 Ctsk 谱系骨膜细胞的募集。 Ctsk 谱系 PSC 表达 PTH 受体，PTH 治疗会增加 PSC 的百分比，这是在缺乏 Sfrp4 的情况下不会出现的反应。重要的是，在缺乏 Sfrp4 的情况下，PTH 依赖性的皮质厚度增加和骨膜骨形成明显受损。因此，这项研究提供了对分泌性局部因子对特定骨膜细胞群的调节的见解，并显示了 Sfrp4 在调节 Ctsk 谱系骨膜干细胞分化和功能中的核心作用。

We have previously reported that the cortical bone thinning seen in mice lacking the Wnt signaling antagonist Sfrp4 is due in part to impaired periosteal apposition. The periosteum contains cells which function as a reservoir of stem cells and contribute to cortical bone expansion, homeostasis, and repair. However, the local or paracrine factors that govern stem cells within the periosteal niche remain elusive. Cathepsin K (Ctsk), together with additional stem cell surface markers, marks a subset of periosteal stem cells (PSCs) which possess self-renewal ability and inducible multipotency. Sfrp4 is expressed in periosteal Ctsk-lineage cells, and Sfrp4 global deletion decreases the pool of PSCs, impairs their clonal multipotency for differentiation into osteoblasts and chondrocytes and formation of bone organoids. Bulk RNA sequencing analysis of Ctsk-lineage PSCs demonstrated that Sfrp4 deletion down-regulates signaling pathways associated with skeletal development, positive regulation of bone mineralization, and wound healing. Supporting these findings, Sfrp4 deletion hampers the periosteal response to bone injury and impairs Ctsk-lineage periosteal cell recruitment. Ctsk-lineage PSCs express the PTH receptor and PTH treatment increases the % of PSCs, a response not seen in the absence of Sfrp4. Importantly, in the absence of Sfrp4, PTH-dependent increase in cortical thickness and periosteal bone formation is markedly impaired. Thus, this study provides insights into the regulation of a specific population of periosteal cells by a secreted local factor, and shows a central role for Sfrp4 in the regulation of Ctsk-lineage periosteal stem cell differentiation and function.