Fig. 9: Model for how TGFβ1-TRAF3 axis affects bone mass during aging.

During aging, increased TGFβ1 protein levels in the bone microenvironment cause decreased bone mass. TGFβ1 targets mesenchymal progenitor cells (MPCs) by binding to its receptors to trigger TRAF3 degradation, leading to excessive NF-κB-mediated CCL5 expression by MPCs. TGFβ1⁺CCR5⁺ neutrophils (TCNs), the major cellular source of TGFβ1 in BM, are recruited from peripheral blood into BM during aging, associated with increased CCL5 levels, resulting in inhibited osteoblast (OB) differentiation and enhanced osteoclast (OC) formation. As we reported previously¹⁶, RANKL expression is increased in MPCs because of TRAF3 degradation and enhances osteoclast formation, which promotes release of more TGFβ1 into the bone microenvironment. This model supports a positive feedback loop in which TGFβ1 stimulates TRAF3 degradation and CCL5 expression by MPCs, and recruits more TCNs into BM. Interventions, such as specific deletion of TGFβRII expression by MPCs or CCR5 blockade by maraviroc, interrupt the positive feedback, and thus inhibit osteoclastogenesis and enhance osteoblast formation.