CORONAVIRUS INFECTION ACCELERATES EXPERIMENTAL OSTEOPOROSIS THROUGH THE ACTIVATION OF OSTEOCLASTS

Abstract

Coronavirus infection is increasingly associated with systemic inflammation and extrapulmonary sequelae, including bone loss. However, the impact of coronavirus infection on hosts with pre-existing osteoporosis remains poorly understood. Here, we investigated the effects of infection with the murine coronavirus MHV-A59 on bone remodeling in a mouse model of ovariectomy-induced osteoporosis. Female C57BL/6 mice underwent ovariectomy (OVX) or sham surgery and, after establishment of the osteoporotic phenotype (14 days post-surgery), were intranasally infected with MHV-A59. Clinical, inflammatory, and femur parameters were evaluated throughout acute and chronic phases of infection using histopathological, micro-computed tomography and biochemical analyses. In vitro infection assays with bone-marrow derived macrophages (BMDM) and BMDM-differentiated osteoclasts from Sham and OVX mice were also performed. MHV-A59 induced comparable lung inflammation in Sham and OVX mice. In contrast, infection accelerated bone resorption in OVX mice during the acute phase (5 dpi), whereas in non-osteoporotic animals, infection induced significant bone loss at later stages (60 dpi). These alterations were associated with increased osteoclast differentiation and activity and with elevated levels of osteometabolic and inflammatory mediators, including RANKL, CCL2, CCL3, CCL5, and TGF-{beta}1. In vitro, MHV-A59 infection enhanced the expression of osteoclast-associated markers, including Rank, Traf6, Nfac1, and cathepsin K, and inflammatory mediators by BMDM and osteoclasts. Importantly, these responses were significantly more pronounced in cells derived from OVX mice. Collectively, our findings demonstrate that coronavirus infection promotes bone resorption and accelerates early bone loss in the context of estrogen deficiency, highlighting enhanced osteoclast activity as a potential mechanism underlying this infection-induced phenotype.