Exosome-based <i>Sfrp2</i> inhibition in mesangial cells alleviates osteoporosis and promotes osteointegration in diabetic kidney disease

Diabetic kidney disease (DKD) and osteoporosis are closely linked, yet the underlying mechanisms remain incompletely understood. DKD mouse and rat models were established via combinatorial treatment with a high-fat diet and streptozotocin, which not only induced progressive renal dysfunction, but also triggered systemic osteoporotic changes, including reduced bone mineral density, trabecular thinning and impaired bone microarchitecture. Using single-cell sequencing, we demonstrate that DKD elevates the expression of <i>Sfrp2</i> (secreted frizzled related protein 2) in glomerular mesangial cells (MCs), establishing MCs as a critical source of circulating secreted frizzled related protein 2 (SFRP2 protein). In turn, elevated SFRP2 potently inhibits the Wnt signaling pathway, suppresses osteoblast differentiation and promotes bone loss in diabetic mice. Exosomes, which exhibit a size range endowed with natural tropism for the renal mesangial space, hold promise as optimal delivery vectors targeting renal MCs. Exosomes loaded with <i>siSfrp2</i> (siRNA against <i>Sfrp2</i> mRNA) circulate into MCs after tail vein injection. In turn, exosome-mediated <i>siSfrp2</i> delivery effectively reduces circulating SFRP2 levels, restores Wnt signaling and alleviates osteoporotic phenotypes in DKD mice. Moreover, in diabetic rat models, renal injury is accompanied by consistent osteoporotic defects and weakened implant osteointegration capacity. Exosome-mediated <i>Sfrp2</i> knockdown in these rats significantly enhances implant osseointegration, further validating the renal-osteal axis. These findings establish a MCs-derived SFRP2-mediated renal-osteal axis, revealing that glomerular MC-secreted SFRP2 serves as a key molecular bridge linking kidney injury to bone loss. This mechanistic insight highlights SFRP2 and its main cellular source (MCs) as promising therapeutic targets for managing diabetic osteoporosis.