Lysine-specific demethylase 1 inhibitor rescues the osteogenic ability of mesenchymal stem cells under osteoporotic conditions by modulating H3K4 methylation

Abstract

Bone tissue engineering may be hindered by underlying osteoporosis because of a decreased osteogenic ability of autologous seed cells and an unfavorably changed microenvironment in these patients. Epigenetic regulation plays an important role in the developmental origins of osteoporosis; however, few studies have investigated the potential of epigenetic therapy to improve or rescue the osteogenic ability of bone marrow mesenchymal stem cells (BMMSCs) under osteoporotic conditions. Here, we investigated pargyline, an inhibitor of lysine-specific demethylase 1 (LSD1), which mainly catalyzes the demethylation of the di- and mono-methylation of H3K4. We demonstrated that 1.5 mmol·L⁻¹ pargyline was the optimal concentration for the osteogenic differentiation of human BMMSCs. Pargyline rescued the osteogenic differentiation ability of mouse BMMSCs under osteoporotic conditions by enhancing the dimethylation level of H3K4 at the promoter regions of osteogenesis-related genes. Moreover, pargyline partially rescued or prevented the osteoporotic conditions in aged or ovariectomized mouse models, respectively. By introducing the concept of epigenetic therapy into the field of osteoporosis, this study demonstrated that LSD1 inhibitors could improve the clinical practice of MSC-based bone tissue engineering and proposes their novel use to treat osteoporosis.

Osteoporosis: histone-modifying therapy promotes bone formation

A drug that affects chemical modification of histones could enhance the bone-forming ability of stem cells. Yongsheng Zhou and colleagues from the Peking University School and Hospital of Stomatology in Beijing, China, treated human and mouse bone marrow-derived stem cells with pargyline, a decades-old blood-pressure drug that blocks an enzyme involved in stripping methyl tags from the histones. This enhanced the expression of bone-promoting genes, even under conditions designed to simulate the bone-thinning disease osteoporosis. The researchers showed that pargyline could also partially rescue or prevent osteoporosis in mouse models. The findings suggest that manipulating histone modification with pargyline or similar agents could improve bone therapies that involve tissue engineering with stem cells, or could be used as a clinical treatment for patients with osteoporosis.

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