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Melatonin activates mitochondrial unfolded protein response to preserve osteogenic potential of senescent BMSCs via upregulating PDI-6

Bone marrow stromal cells (BMSCs) possess the capability to differentiate into osteogenic or adipogenic lineages. With aging, BMSCs suffer from mitochondrial dysfunction and undergo senescence, favoring adipogenesis at the expense of osteoblastogenesis. It leads to decreased bone formation and contributes to senile osteoporosis (SOP). In the current study, RNA-seq analysis unveiled that senescent BMSCs from mice exhibited a significant suppression in the expression of the protein disulfide isomerase PDI-6, an important regulator of mitochondrial unfolded protein response (UPRmt) as well as maintenance of mitochondrial homeostasis. Overexpression of PDI-6 in senescent BMSCs partially rescued mitochondrial function and enhanced osteogenic differentiation. In contrast, osteoblastogenesis of BMSCs remarkably deteriorated under the condition of PDI-6 silencing. Furthermore, melatonin, an endocrine hormone, effectively enhanced PDI-6 expression and repaired injured mitochondria, and the effect of melatonin on PDI-6 expression was melatonin receptor dependent. We further identified that PDI-6 was a downstream effector of Wnt/β-catenin pathway, as the inhibitor of Wnt3A/TCF signaling, Wnt-C59, inhibited PDI-6 expression. Potential β-catenin-TCF/LEF binding sites on the promoter of PDI-6 gene were also validated by chromatin immunoprecipitation (ChIP) assay. Thus, our study suggests that PDI-6 is a pharmacological target of melatonin for the intervention of age-related osteoporosis via mitigating mitochondrial dysfunction in senescent BMSCs.

 

Comments：

PDI-6, a regulator of mitochondrial function, is a potential target for melatonin intervention to mitigate mitochondrial dysfunction in senescent bone marrow stromal cells and improve osteoblastogenesis for the treatment of age-related osteoporosis.

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Cat.No. Product Name Information
S1204 Melatonin Melatonin is a MT receptor agonist, used as a dietary supplement. Melatonin is a selective ATF-6 inhibitor and downregulates COX-2. Melatonin enhances mitophagy and regulates the homeostasis of apoptosis and autophagy.

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COX Apoptosis related Autophagy Mitophagy MT Receptor