Multiple myeloma bone disease is characterized by the development of osteolytic bone lesions. Recent work identified matrix metalloproteinase 13 as a myeloma-derived fusogen that induces osteoclast activation independent of its proteolytic activity. We now identify programmed death-1 homolog, PD-1H, as the bona fide MMP-13 receptor on osteoclasts. Silencing PD-1H or using Pd-1h^-/- bone marrow cells abrogates the MMP-13-enhanced osteoclast fusion and bone-resorptive activity. Further, PD-1H interacts with the actin cytoskeleton and plays a necessary role in supporting c-Src activation and sealing zone formation. The critical role of PD-1H in myeloma lytic bone lesions was confirmed using a Pd-1h^-/- myeloma bone disease mouse model wherein myeloma cells injected into Pd-1h^-/-Rag2^-/- results in attenuated bone destruction. Our findings identify a role of PD-1H in bone biology independent of its known immunoregulatory functions and suggest that targeting the MMP-13/PD-1H axis may represent a potential approach for the treatment of myeloma associated osteolysis.

多发性骨髓瘤骨病的特征是溶骨性骨病变的发展。最近的工作确定基质金属蛋白酶 13 是一种骨髓瘤衍生的梭原，可诱导破骨细胞活化，而与其蛋白水解活性无关。我们现在确定程序性死亡 1 同源物 PD-1H 是破骨细胞上真正的 MMP-13 受体。沉默 PD-1H 或使用 Pd-1h^-/-骨髓细胞可消除 MMP-13 增强的破骨细胞融合和骨吸收活性。此外，PD-1H 与肌动蛋白细胞骨架相互作用，并在支持 c-Src 激活和密封区形成中发挥必要作用。使用 Pd-1h^-/-骨髓瘤骨病小鼠模型证实了 PD-1H 在骨髓瘤溶骨病变中的关键作用，其中骨髓瘤细胞注射到 Pd-1h^-/-Rag2^-/- 中导致骨破坏减弱。我们的研究结果确定了 PD-1H 在骨生物学中的作用，独立于其已知的免疫调节功能，并表明靶向 MMP-13/PD-1H 轴可能代表了治疗骨髓瘤相关骨溶解的潜在方法。