CREG1 alleviates bone loss in osteoporosis by enhancing the osteogenic differentiation of BMSCs through mitophagy

The pathological process of osteoporosis involves accelerated bone resorption and a decline in bone formation, among which the disruption of the balance between adipogenic and osteogenic differentiation in bone marrow mesenchymal stem cells (BMSCs) is a crucial part. Cellular repressor of E1A-stimulated genes 1 (CREG1), a small glycoprotein, is mainly localized to the endosomal-lysosomal compartment and is associated with the regulation of mitophagy and cell differentiation. However, its roles in BMSCs osteogenic differentiation and skeletal degenerative disorders, including osteoporosis, are poorly understood. We previously identified CREG1 as being highly expressed in the bone marrow through database analysis and found that its expression increased in the process of BMSCs osteogenic differentiation. In the present study, we demonstrated that the expression of CREG1 was reduced in osteoporosis patients and animal models, and the overexpression of CREG1 contributed to higher bone mass compared with ovariectomy (OVX)-induced bone loss models. Further research revealed that the knockdown of CREG1 inhibited the osteogenic differentiation of BMSCs, while CREG1 overexpression promoted this process. Additionally, we found that CREG1 overexpression was accompanied by an increase in mitophagy levels, and the osteogenic differentiation induced by this overexpression was blocked when mitophagy was inhibited, indicating that CREG1 promoted osteogenic differentiation through inducing mitophagy. Therefore, our findings demonstrated that CREG1 is involved in regulating the osteogenic differentiation of BMSCs, thereby providing new therapeutic targets and pathways for the treatment of osteoporosis.