Endogenous retrotransposon activity supports osteocyte function and links antiretroviral therapy to bone loss

Retrotansposable elements such as LINE-1 and HERV-K encode endogenous reverse transcriptases (RTs) with emerging roles in human biology. People living with HIV, particularly those receiving nucleoside reverse transcriptase inhibitor (NRTI)-based therapy, have increased risk of low bone mineral density (BMD), but the underlying mechanisms remain unclear. Here we show that endogenous RT activity, estimated by L1-Ta and HERV-K DNA content, is enriched in human bone and markedly reduced in osteoporosis, where it correlates with BMD and osteocyte gene expression. In vitro, nucleoside reverse transcriptase inhibitors (NRTIs), widely used as antiretroviral drugs, impair osteocyte endocrine function, disrupting vitamin D3-induced FGF23 production and parathyroid hormone- mediated regulation of SOST. These findings identify endogenous RT activity as a regulator of osteocyte function and bone homeostasis, and suggest that its pharmacological inhibition may contribute to antiretroviral therapy-associated bone loss.