Combination of metformin and exercise alleviates osteoarthritis in ovariectomized mice fed a high-fat diet.

Abstract

To evaluate and compare the effects of the combined intervention of metformin and exercise on the degeneration of cartilage and subchondral bone in a mouse model of osteoarthritis (OA) induced by estrogen deficiency and obesity. 56 female 3-month-old C57BL/6 mice underwent ovariectomy (OVX) (n=40) or a sham operation (n=16) and were randomized into seven groups (n=8/group): 1) sham-operated mice with a normal diet (Sham), 2) OVX mice with a normal diet (OVX), 3) sham-operated mice with high-fat diet (HFD) (HSVX), 4) OVX mice with HFD (HOVX), 5) OVX mice with HFD+exercise (HOVE), 6) OVX mice with HFD+metformin (HOMX), and 7) OVX mice with HFD+metformin+exercise (HOME). Drug administration and exercise training were initiated 72h after surgical operation. The pathology of OA was assessed by histomorphology analyses, immunohistochemistry (IHC), tartrate-resistant acid phosphatase (TRAP) staining, micro-computed tomography and enzyme-linked immunosorbent assay (ELISA). Histomorphological analysis revealed that OA was significantly exacerbated by the coexistence of estrogen deficiency and obesity and markedly alleviated by the combined intervention. In details, metformin plus exercise ameliorated the abnormal metabolic status and cartilage lesions, significantly increased aggrecan and collagen-II expression and decreased the expression of ADAMTS-4. Furthermore, combined intervention markedly improved bone degeneration, bone mass and microarchitecture of subchondral bone. And the intervention also increased the concentration of OCN and decreased the serum concentration of IL-1β and CTX-1 and glucose. The coexistence of estrogen deficiency and obesity further aggravates abnormal metabolic pathology and articular degeneration, which could be prevented by the combination with metformin and exercise, suggesting that combined intervention may be a potential candidate for amelioration of the progression of OA.