Osteoprotegerin (OPG) is a circulating decoy receptor for RANKL, a multifunctional cytokine essential for the differentiation of tissue-specific cells in bone and immune systems such as osteoclasts, medullary thymic epithelial cells (mTECs), and intestinal microfold cells (M cells). However, it is unknown whether OPG functions only at the production site or circulates to other tissues acting in an endocrine fashion. Here we explore the cellular source of OPG by generating OPG-floxed mice and show that locally produced OPG, rather than circulating OPG, is crucial for bone and immune homeostasis. Deletion of OPG in osteoblastic cells leads to severe osteopenia without affecting serum OPG. Deletion of locally produced OPG increases mTEC and M cell numbers while retaining the normal serum OPG level. This study shows that OPG limits its functions within the tissue where it was produced, illuminating the importance of local regulation of the RANKL system.

骨保护素（OPG）是RANKL的循环诱饵受体，RANKL是一种多功能细胞因子，对于骨骼和免疫系统中的组织特异性细胞的分化至关重要，例如破骨细胞，髓样胸腺上皮细胞（mTECs）和肠微折叠细胞（M细胞）。然而，OPG是仅在生产现场起作用还是循环到以内分泌方式起作用的其他组织尚不清楚。在这里，我们通过产生OPG固定的小鼠来探索OPG的细胞来源，并显示本地产生的OPG（而不是循环的OPG）对于骨骼和免疫稳态至关重要。成骨细胞中OPG的缺失会导致严重的骨质减少，而不会影响血清OPG。删除局部产生的OPG可增加mTEC和M细胞数量，同时保持正常的血清OPG水平。