Mitochondrial Phosphoenolpyruvate Carboxykinase (PCK2) Maintains the Function of Bone Marrow Mesenchymal Stromal/stem Cells to Rescue Osteoporotic Phenotype Partly Through Autophagy Dependent Manner

Abstract BackgroundMitochondrial phosphoenolpyruvate carboxykinase (PCK2) is a rate-limiting enzyme that plays critical roles in multiple physiological processes. We unveiled the important role of PCK2 on the regulation of osteogenesis by mesenchymal stromal/stem cells (MSCs) in our previous work. Here we further investigated the roles of PCK2 on regulating adipogenesis of MSCs and its therapeutic effect on osteoporosis. MethodsWe investigated PCK2 function in adipogenic differentiation of MSCs in vitro through loss-and-gain-of-function experiments. This was followed by heterotopic adipose formation assay in nude mice. In addition, ovariectomized (OVX) and aged mice were used as osteoporotic models to test the effect of PCK2 on osteoporosis. The bone formation and adipocyte accumulation were assessed by micro-CT and histological analysis. The multipotent capacity of control and osteoporotic BMMSCs were evaluated by quantitative real time-polymerase chain reaction (qRT-PCR) and western blot analysis. ResultsPCK2 expression levels were significantly decreased in BMMSCs from OVX and aged mice. Furthermore, PCK2 could inhibit adipogenesis of BMMSCs and thus resisting lipid droplet formation and attenuating bone loss in osteoporotic mice. Mechanistically, we detected that autophagy level was decreased in BMMSCs of osteoporotic mice, while overexpression of PCK2 in vivo could rescued the autophagy activity. We further indicated that PCK2 could reverse osteopenia phenotype and adipose formation in OVX and aged mice partially via autophagy.ConclusionsCollectively, we suggested that PCK2 could attenuate bone loss and adipocyte accumulation of BMMSCs in osteoporotic mice through autophagy dependent manner. Our study indicated that PCK2 could be a brand and effective therapeutic target for osteoporosis treatment.