Lumican stimulates osteogenic differentiation in bone marrow-derived mesenchymal stem cells through glycolytic reprogramming to alleviate osteoporosis.
Heqing Huang, Lei Xiang, Wei Liu, Congcong Zeng, Zhitao Liu
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引用次数: 0
Abstract
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.
期刊介绍：
The aim of Connective Tissue Research is to present original and significant research in all basic areas of connective tissue and matrix biology.
The journal also provides topical reviews and, on occasion, the proceedings of conferences in areas of special interest at which original work is presented.
The journal supports an interdisciplinary approach; we present a variety of perspectives from different disciplines, including
Biochemistry
Cell and Molecular Biology
Immunology
Structural Biology
Biophysics
Biomechanics
Regenerative Medicine
The interests of the Editorial Board are to understand, mechanistically, the structure-function relationships in connective tissue extracellular matrix, and its associated cells, through interpretation of sophisticated experimentation using state-of-the-art technologies that include molecular genetics, imaging, immunology, biomechanics and tissue engineering.
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