Lumican stimulates osteogenic differentiation in bone marrow-derived mesenchymal stem cells through glycolytic reprogramming to alleviate osteoporosis

PURPOSE: Lumican, a small leucine-rich proteoglycan, is implicated in diverse biological functions. This study investigates the role of lumican in osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs) and its therapeutic efficacy against osteoporosis (OP), while preliminarily elucidating its mechanism. MATERIALS AND METHODS: hBMSCs were cultured under osteogenic induction. Cell proliferation and migration were assessed using CCK-8 and Transwell assays. Osteogenic differentiation was evaluated by ALP/ARS staining, with osteogenic marker genes (Runx2, Osterix, OCN) measured via RT-qPCR. An ovariectomized (OVX) rat OP model was established. Bone microstructure was analyzed by HE staining and serum OCN levels by ELISA. Glycolysis was assessed through glucose uptake, lactate production, ATP levels, and key glycolytic enzyme expression. The glycolytic inhibitor 2-DG was used for rescue experiments. Histone lactylation (H3K18la) and its promoter enrichment were analyzed by Western blot and ChIP. RESULTS: Lumican expression increased during osteogenic induction and dose-dependently enhanced hBMSC proliferation, migration, and osteogenic differentiation. ALP/ARS staining showed. Enhanced osteogenic differentiation, while RT-qPCR further confirmed upregulated Runx2, Osterix, and OCN. In OVX rats, lumican improved trabecular microstructure and increased serum OCN and osteogenic gene expression in bone tissues. Mechanistically, lumican promoted glycolysis in hBMSCs, indicated by increased glucose uptake, lactate production, ATP levels, and glycolytic enzyme expression. The lumican-induced osteogenic effects were abolished by 2-DG. Furthermore, lumican enhanced histone lactylation, particularly increasing H3K18la enrichment at osteogenic gene promoters, which was suppressed by 2-DG. CONCLUSIONS: Lumican promotes hBMSC osteogenic differentiation and ameliorates OP by enhancing glycolysis and histone lactylation, providing a potential therapeutic target.