TNF/TNFR modulates the Traf2-Gαs axis to promote aging-related bone loss and impair PTH (1-34) efficacy

The anti-osteoporotic effects of parathyroid hormone (PTH) analogs for patients with severe osteoporosis decrease with age; however, the underlying mechanism(s) are poorly understood. Here we provide evidence that enhanced TNF-mediated chronic inflammation during aging may play a critical role in promoting bone loss and attenuating the anabolic effects of PTH on bone in aged individuals. Specifically, we find that abolishment of TNF signaling activation by global deletion of the Tnfr1/2 genes, which encode the TNF receptors, prevents aging-related bone mass loss and improves the anabolic effects of PTH (1-34) analog to increase bone mass and bone mineral density in aged, but not young adult, mice. These effects are achieved mainly by enhancing PTH signaling in osteoblastic cells, leading to accelerated bone formation. TNF-α inhibition of PTH signaling is mediated via TRAF2, an E3 ligase. TRAF2 promotes the non-canonical K27- and K33-linked ubiquitination of Gαs, which increases Gαs protein stability but blocks Gαs activation and downstream signaling. Of clinical significance, infliximab, a TNF-α neutralizing antibody, reduces the bone loss in aged mice and improves the skeletal response to PTH. Collectively, we demonstrate a novel mechanism whereby TNF/TNFR/TRAF2 promotes aging-related bone loss and impairs the anabolic effects of PTH on bone in aged animals by inhibiting Gαs activation, and our findings suggest that modulating the TNF/TNFR signaling pathway may improve the effectiveness of PTH treatment in senile osteoporosis patients.