Pulsed electromagnetic fields attenuate glucocorticoid-induced bone loss by targeting senescent LepR+ bone marrow mesenchymal stromal cells

Abstract

Glucocorticoids induce cellular senescence, including of stem/progenitor cells in the bone marrow of growing long bone, which leads to bone loss in glucocorticoid–induced osteoporosis. There is no specific drug available to treat this disease. Clearance of senescent cells has been reported to be an effective therapy for osteoporosis. LepR+ cells in the bone marrow are the key kind of stem/progenitor cells conducive to bone remodeling in adulthood. Here, we show that glucocorticoids induce cellular senescence, demonstrated by increased activity of senescence-associated β-galactosidase (SA-βGal+) cells and simultaneous upregulation of coimmunofluorescence staining of p16INK4a with LepR in longitudinal femoral sections. We applied pulsed electromagnetic fields (PEMFs), which alleviated bone loss in glucocorticoid-induced osteoporosis mice. We found the increased accumulation of senescent LepR+ cells in the bone marrow of adult mice after glucocorticoid treatment, and this could be counteracted by PEMFs. Moreover, PEMFs maintained type H vessel formation and osteogenesis. This process was modulated by the polycomb histone methyltransferase enhancer of zeste homolog 2 (EZH2) and its trimethylation of histone H3 on lysine 27 (H3K27me3). These results provide evidence that PEMFs alleviate bone loss induced by glucocorticoids by eliminating senescent cells, maintaining angiogenesis-osteogenesis coupling, and shedding light on the mechanisms, providing a potential method to treat glucocorticoid-induced osteoporosis.