Abstract
Inflammaging induces osteoporosis by promoting bone destruction and inhibiting bone formation. TRAF3 limits bone destruction by inhibiting RANKL-induced NF-κB signaling in osteoclast precursors. However, the role of TRAF3 in mesenchymal progenitor cells (MPCs) is unknown. Mice with TRAF3 deleted in MPCs develop early onset osteoporosis due to reduced bone formation and enhanced bone destruction. In young mice TRAF3 prevents β-catenin degradation in MPCs and maintains osteoblast formation. However, TRAF3 protein levels decrease in murine and human bone samples during aging when TGFβ1 is released from resorbing bone. TGFβ1 induces degradation of TRAF3 in murine MPCs and inhibits osteoblast formation through GSK-3β-mediated degradation of β-catenin. Thus, TRAF3 positively regulates MPC differentiation into osteoblasts. TRAF3 deletion in MPCs activated NF-κB RelA and RelB to promote RANKL expression and enhance bone destruction. We conclude that pharmacologic stabilization of TRAF3 during aging could treat/prevent age-related osteoporosis by inhibiting bone destruction and promoting bone formation.
Highlights
Inflammaging induces osteoporosis by promoting bone destruction and inhibiting bone formation
It is associated with sex steroid deficiency[4] and low-grade chronic inflammation of aging[5,6]. These are accompanied by increased production of pro-inflammatory cytokines, including TNF, IL-1, and IL-65,6, which increase the expression of RANKL, a TNF superfamily member that is expressed by osteoblastic[7] and immune cells[8,9] in bone marrow (BM) and is required for osteoclastogenesis[4,10,11]
To determine if TRAF3 has a role in osteoblastic bone formation, we crossed Traf3flox/flox mice[14,21] with Prx1cre mice to generate Traf3f/fPrx1cre mice with TRAF3 conditionally deleted in mesenchymal progenitor cells (MPCs)
Summary
Inflammaging induces osteoporosis by promoting bone destruction and inhibiting bone formation. Mice with TRAF3 deleted in MPCs develop early onset osteoporosis due to reduced bone formation and enhanced bone destruction. Mice with TRAF3 conditionally deleted in myeloid progenitor cells (which include OCPs) develop early onset osteoporosis due to increased bone resorption, indicating that TRAF3 expression in these cells limits age-related bone loss[14]. We found that TRAF3 protein levels are lower in the bone and BM of old than young WT mice and, importantly, in samples of bone from older adults than from children These findings suggest that prevention of TRAF3 degradation in bone cells could be a novel therapeutic approach to prevent age-related osteoporosis
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