Autophagy Maintains the Function of Bone Marrow Mesenchymal Stem Cells to Prevent Estrogen Deficiency-Induced Osteoporosis

Abstract

Rationale: The impaired function of endogenous bone marrow mesenchymal stem cells (BMMSCs) is a determinant in the development of osteoporosis (OP). Recent researches have proved that autophagy plays an important role in maintenance of skeletal phenotype. However, whether autophagy affects the development of OP through regulating the function of BMMSCs remains elusive.Methods: Ovariectomy (OVX)-induced OP model and sham model were established in 8-week-old C57 mice. The differentiation and immunoregulation properties of BMMSCs from two models were examined by osteogenic/adipogenic induction in vitro and treatment of a dextran sulfate sodium (DSS)-induced mice colitis model in vivo. We evaluated autophagy activity in sham and OVX BMMSCs by quantitative real time-polymerase chain reaction (qRT-PCR), western blotting, laser confocal microscopy and transmission electron microscopy (TEM). Finally, to testify the effects of rapamycin, short hairpin RNA (shRNA) -BECN1 (shBECN1) and shRNA-ATG5 (shATG5), we performed Alizarin Red staining and Oil Red O staining to detect lineage differentiations of BMMSCs, and carried out micro-CT, calcein staining and Oil Red O staining to assess the skeletal phenotype.Results: BMMSCs from OVX-induced OP model mice exhibited decreased osteogenic differentiation, increased adipogenic differentiation and impaired immunoregulatory capacity. Furthermore, autophagy decreased both in bone marrow and BMMSCs of osteoporotic mice. Importantly, regulation of autophagy directly affects the functions of BMMSCs, including differentiation and immunoregulatory capacities. Moreover, treatment with rapamycin rescued the function of endogenous BMMSCs and attenuated the osteoporotic phenotype in OVX mice.Conclusion: Our findings suggest that autophagy regulates the regenerative function of BMMSCs and controls the development of OP. The restoration of autophagy by rapamycin may provide an effective therapeutic method for osteoporosis.

Mitochondrial Phosphoenolpyruvate Carboxykinase Regulates Osteogenic Differentiation by Modulating AMPK/ULK1-Dependent Autophagy

“…Interestingly, through exploring potential mechanisms, we observed a positive regulatory effect of PCK2 on autophagy during osteogenesis by MSCs. A recent study demonstrated that depletion of autophagy-related-genes, such as ATG5 and BECN, leads to impaired osteogenic ability of BMSCs in vivo [9]. In accordance with this study, we found that autophagy was indispensable for the osteogenesis by MSCs.…”

“…The activation of autophagy promotes the osteogenic ability of hBMSCs from osteoporotic vertebrae [22]. Moreover, a recent study showed that diminished lineage differentiation could be partly rescued by activation of autophagy in osteoporotic BMSCs [9]. Investigations on the involvement of autophagy in hASCs have displayed similar results.…”

“…Activation of autophagy was reported to significantly increase osteogenic differentiation and could rescue bone volume (BV) . Impaired autophagy was also found in the well‐known skeletal degenerative diseases—osteoporosis . These studies suggest that autophagy, as a vital link in the chain of energy metabolism, has a profound impact on the osteogenesis by MSCs.…”

Relationship between autophagy, apoptosis and endoplasmic reticulum stress induced by melatonin in osteoblasts by septin7 expression

“…For example, autophagy attenuates oxidative stress-induced apoptosis of Mc3T3-e1 osteoblasts (40). Qi et al (41) indicated that autophagy maintains the function of bone marrow mesenchymal stem cells to prevent estrogen deficiency-induced osteoporosis. The present findings showed that autophagy was triggered when osteoblasts were treated with melatonin, and the degree of autophagy increased gradually over time, as shown by the autophagy marker lc3-ii.…”

GOLM1 Stimulation of Glutamine Metabolism Promotes Osteoporosis via Inhibiting Osteogenic Differentiation of BMSCs

“…Some studies have revealed that abnormal differentiation of BMSCs promotes the development of osteoporosis [10]. A previous study found that autophagy prevented estrogen deficiency-induced osteoporosis through maintaining the function of bone marrow mesenchymal stem cells [11]. Clinical studies have also demonstrated that postmenopausal osteoporotic women exhibit an adipogenic differentiation of BMSCs [1,12].…”