Fibrous scars frequently form at the sites of bone nonunion when attempts to repair bone fractures have failed. However, the detailed mechanism by which fibroblasts, which are the main components of fibrous scars, impede osteogenesis remains largely unknown. In this study, we found that fibroblasts compete with osteogenesis in both human bone nonunion tissues and BMP2-induced ectopic osteogenesis in a mouse model. Fibroblasts could inhibit the osteoblastic differentiation of mesenchymal stem cells (MSCs) via direct and indirect cell competition. During this process, fibroblasts modulated the nuclear-cytoplasmic shuttling of YAP in MSCs. Knocking down YAP could inhibit osteoblast differentiation of MSCs, while overexpression of nuclear-localized YAP-5SA could reverse the inhibition of osteoblast differentiation of MSCs caused by fibroblasts. Furthermore, fibroblasts secreted DKK1, which further inhibited the formation of calcium nodules during the late stage of osteogenesis but did not affect the early stage of osteogenesis. Thus, fibroblasts could inhibit osteogenesis by regulating YAP localization in MSCs and secreting DKK1. Our research revealed that fibroblasts could modulate the nuclear-cytoplasmic shuttling of YAP in MSCs, thereby inhibiting their osteoblast differentiation. Fibroblasts could also secrete DKK1, which inhibited calcium nodule formation at the late stage of osteogenesis.

中文翻译：

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成纤维细胞通过调节间充质干细胞中 YAP 的核细胞质穿梭并分泌 DKK1 抑制成骨

当尝试修复骨折失败时，骨不连部位经常会形成纤维疤痕。然而，作为纤维疤痕的主要成分的成纤维细胞阻碍成骨的详细机制仍然很大程度上未知。在这项研究中，我们发现成纤维细胞与人骨不连组织中的成骨作用以及小鼠模型中 BMP2 诱导的异位成骨作用竞争。成纤维细胞可以通过直接和间接的细胞竞争抑制间充质干细胞（MSC）的成骨细胞分化。在此过程中，成纤维细胞调节 YAP 在 MSC 中的核质穿梭。敲低YAP可以抑制MSCs的成骨细胞分化，而核定位的YAP-5SA的过表达可以逆转成纤维细胞引起的MSCs成骨细胞分化的抑制。此外，成纤维细胞分泌DKK1，进一步抑制成骨后期钙结节的形成，但不影响成骨早期。因此，成纤维细胞可以通过调节 YAP 在 MSC 中的定位并分泌 DKK1 来抑制成骨。我们的研究表明，成纤维细胞可以调节 MSC 中 YAP 的核质穿梭，从而抑制其成骨细胞分化。成纤维细胞还可以分泌DKK1，抑制成骨后期钙结节的形成。