Bone degradation machinery of osteoclasts: An HIV-1 target that contributes to bone loss

Abstract

Bone deficits are frequent in HIV-1-infected patients. We report here that osteoclasts, the cells specialized in bone resorption, are infected by HIV-1 in vivo in humanized mice and ex vivo in human joint biopsies. In vitro, infection of human osteoclasts occurs at different stages of osteoclastogenesis via cell-free viruses and, more efficiently, by transfer from infected T cells. HIV-1 infection markedly enhances adhesion and osteolytic activity of human osteoclasts by modifying the structure and function of the sealing zone, the osteoclast-specific bone degradation machinery. Indeed, the sealing zone is broader due to F-actin enrichment of its basal units (i.e., the podosomes). The viral protein Nef is involved in all HIV-1-induced effects partly through the activation of Src, a regulator of podosomes and of their assembly as a sealing zone. Supporting these results, Nef-transgenic mice exhibit an increased osteoclast density and bone defects, and osteoclasts derived from these animals display high osteolytic activity. Altogether, our study evidences osteoclasts as host cells for HIV-1 and their pathological contribution to bone disorders induced by this virus, in part via Nef.

HIV-1-infected human macrophages, by secreting RANKL, contribute to enhanced osteoclastogenesis

“…In accordance with this proposal, HIV-1-transgenic rats have a reduced bone mass as a consequence of an increased number of OC [18]. Furthermore, transgenic mice expressing the viral protein Nef, a key actor in the bone resorption activity of HIV-1-infected OC, exhibited a reduced bone density and a marked increase in OC compared with controls [21]. In conclusion, in addition to the mechanisms described previously by us and others [5,17,21], this study identifies a novel mechanism (i.e.…”

“…To this end, OC precursors were differentiated in the presence of CmHIV or CmCTL, and the fusion index (as a parameter for OC differentiation) and bone degradation were measured. As infection of OC precursors promotes their differentiation [21], OC precursors were pre-treated, before addition of conditioned media ,with maraviroc to prevent HIV-1 entry. The fusion of OC precursors and bone degradation were not significantly increased by incubation with CmHIV compared to CmCTL ( Fig.…”

“…Finally, we tested whether CmHIV could impact the migration of OC precursors. The recruitment of OC precursors from blood to bones requires proteases in vivo [40], and we showed previously that defects in the 3 dimensional (3D) protease-dependent mesenchymal migration of these cells in vitro correlates with lower recruitment of OC to bones in vivo [21,41]. In Matrigel, human OC precursors use the mesenchymal migration [42,43].…”

“…Today, only a few mechanisms have been proposed to explain the increase in osteolytic activity associated with HIV-1 infection comprising increased production of proinflammatory cytokines [15], disruption of the immune system [5,[16][17][18]and activation of the bone resorption activity of infected OC [19][20][21]. Through its action on T and B cells, HIV-1 infection leads to an increase in the RANKL/OPG ratio that stimulates OC differentiation [5,17].…”

“…These changes markedly correlate with an enhanced OC adhesion and bone degradation capacity. This exacerbated osteolytic activity of infected OC is dependent on Src activation by the viral protein Nef [21].…”