Despite the diverse roles of tripartite motif (Trim)-containing proteins in the regulation of autophagy, the innate immune response, and cell differentiation, their roles in skeletal diseases are largely unknown. We recently demonstrated that Trim21 plays a crucial role in regulating osteoblast (OB) differentiation in osteosarcoma. However, how Trim21 contributes to skeletal degenerative disorders, including osteoporosis, remains unknown. First, human and mouse bone specimens were evaluated, and the results showed that Trim21 expression was significantly elevated in bone tissues obtained from osteoporosis patients. Next, we found that global knockout of the Trim21 gene (KO, Trim21^−/−) resulted in higher bone mass compared to that of the control littermates. We further demonstrated that loss of Trim21 promoted bone formation by enhancing the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and elevating the activity of OBs; moreover, Trim21 depletion suppressed osteoclast (OC) formation of RAW264.7 cells. In addition, the differentiation of OCs from bone marrow-derived macrophages (BMMs) isolated from Trim21^−/− and Ctsk-cre; Trim21^f/f mice was largely compromised compared to that of the littermate control mice. Mechanistically, YAP1/β-catenin signaling was identified and demonstrated to be required for the Trim21-mediated osteogenic differentiation of BMSCs. More importantly, the loss of Trim21 prevented ovariectomy (OVX)- and lipopolysaccharide (LPS)-induced bone loss in vivo by orchestrating the coupling of OBs and OCs through YAP1 signaling. Our current study demonstrated that Trim21 is crucial for regulating OB-mediated bone formation and OC-mediated bone resorption, thereby providing a basis for exploring Trim21 as a novel dual-targeting approach for treating osteoporosis and pathological bone loss.

尽管含有三联基序 (Trim) 的蛋白质在自噬、先天免疫反应和细胞分化的调节中发挥着多种作用，但它们在骨骼疾病中的作用很大程度上未知。我们最近证明 Trim21 在调节骨肉瘤中成骨细胞 (OB) 分化中发挥着至关重要的作用。然而，Trim21 如何导致骨骼退行性疾病（包括骨质疏松症）仍然未知。首先，对人和小鼠的骨标本进行了评估，结果显示，从骨质疏松症患者获得的骨组织中，Trim21 的表达显着升高。接下来，我们发现Trim21基因的整体敲除（KO，Trim21 ^−/−）导致与对照同窝仔鼠相比更高的骨量。我们进一步证明，Trim21的缺失通过增强骨髓间充质干细胞（BMSC）的成骨分化和提高OB的活性来促进骨形成；此外，Trim21 缺失抑制了 RAW264.7 细胞的破骨细胞 (OC) 形成。此外，OCs 与从Trim21 ^−/−和Ctsk-cre分离的骨髓源性巨噬细胞 (BMM) 的分化；与同窝对照小鼠相比，Trim21 ^{f/f小鼠的情况很大程度上受到损害。}从机制上讲，YAP1/β-连环蛋白信号传导被鉴定并证明是 Trim21 介导的 BMSC 成骨分化所必需的。更重要的是，Trim21 的缺失通过 YAP1 信号传导协调 OB 和 OC 的偶联，防止了卵巢切除术 (OVX) 和脂多糖 (LPS) 诱导的体内骨质流失。我们目前的研究表明，Trim21对于调节OB介导的骨形成和OC介导的骨吸收至关重要，从而为探索Trim21作为治疗骨质疏松和病理性骨丢失的新型双靶向方法奠定了基础。