OPG Production Matters Where It Happened

Abstract

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.

Sirt6 Regulates the Development of Medullary Thymic Epithelial Cells and Contributes to the Establishment of Central Immune Tolerance

“…It is nicely demonstrated by Akiyama et al that Spib remarkably limits the development and maturation of mTECs but promotes CD80 expression in mature mTECs (Akiyama et al, 2014). Importantly, RANKL stimulation consecutively induces Spib expression in TECs and Spib facilitates expression of OPG protein, which competitively inhibits RANKL-RANK interactions as a decoy receptor of RANKL, in mTECs by maintenance of the hypomethylated states in Opg (Akiyama et al, 2014;Tsukasaki et al, 2020). Thus, SPIB-mediated negative feedback regulation of RANKL signaling limits mTEC development in neonates but not in embryos by forming RANKL-NF-κB-SPIB-OPG regulating loop in mTECs (Akiyama et al, 2014).…”

The Development of Molecular Biology of Osteoporosis

“…In OPG-floxed mice, it showed that locally produced OPG is important for bone and immune homeostasis rather than circulating OPG. It suggests that OPG limits its role within the tissue where it was produced [ 51 ].…”

Self-emulsified annatto tocotrienol improves bone histomorphometric parameters in a rat model of oestrogen deficiency through suppression of skeletal sclerostin level and RANKL/OPG ratio

“…International Publisher osteoblast lineage cells [13,14]. Persistent elevation of PTH (as in calcium deficiency) causes skeletal catabolic effects by elevating RANKL expression and lowering OPG expression of osteoblasts [15,16].…”

“…Osteoprotegerin (OPG) acts as a decoy receptor of RANKL by preventing the binding between RANK and RANKL. Both cytokines are secreted by osteoblast lineage cells 13 , 14 . Persistent elevation of PTH (as in calcium deficiency) causes skeletal catabolic effects by elevating RANKL expression and lowering OPG expression of osteoblasts 15 , 16 .…”