Osteoclastogenesis with FN1-associated cell differentiation, immune communication, and ECM remodeling in male SAMP6 mice

Abstract

Early diagnosis and precise treatment of senile osteoporosis remain challenging. Herein, we apply a multi-omics strategy, integrating scRNA-seq and proteomics in the male 5-month-old senescence-accelerated mouse prone 6 (SAMP6) spontaneous aging model, to study early bone loss. Through analysis of bone marrow cell heterogeneity, we show that hyperactivated osteoclast differentiation arises at the pre-symptomatic osteopenic stage, while intercellular communication further highlights the involvement of the extracellular matrix (ECM) protein fibronectin (FN1). Ligand-receptor interaction modeling suggests an enriched FN1-CD44 interaction axis between monocytes and neutrophils, potentially driving inflammation, ECM remodeling, and osteoclastogenesis. Plasma proteomic profiling confirms elevated circulating FN1 levels in SAMP6 mice. Functionally, exogenous FN1 treatment promotes osteoclast formation and function in vitro, and disrupting FN1 matrix assembly with RGDS peptides abolishes these effects. Collectively, these findings identify extracellular FN1 as a critical microenvironmental factor and a circulating indicator correlated with osteolytic bone loss, shedding new lights on the diagnosis and therapeutic approaches for osteoporosis.