Disease-Modifying Potential of Metformin and Alendronate in an Experimental Mouse Model of Osteoarthritis

Abstract

Osteoarthritis (OA) is the most common degenerative joint disease causing progressive damages of the cartilage and subchondral bone, synovial inflammation, and severe pain. Despite the complex pathomorphological changes that occur in OA, the approach to different forms of OA is standardized. The global results from pharmacological treatment are not satisfactory. Hence, this study aimed to explore the effects of metformin, alendronate, and their combination on OA development and progression in mice with collagenase-induced osteoarthritis (CIOA). Female ICR (CD-2) mice were randomized to five groups: control group, CIOA untreated, CIOA + metformin, CIOA + alendronate, and CIOA + metformin + alendronate. OA was induced by the intra-articular (i.a.) injection of collagenase. OA phenotype was analyzed by flow cytometry (bone marrow cell differentiation), ELISA (serum levels of the adipokines leptin and resistin), and histology (pathological changes of the knee joint). Treatment with metformin, alendronate, or their combination inhibited the expression of RANK and RANKL on osteoblasts and osteoclasts obtained by ex vivo cultivation of bone marrow cells in mineralization or osteoclastogenic media. In addition, metformin treatment was effective for the attenuation of fibroblast differentiation, but not of mesenchymal stem cells (MSCs), while alendronate had an opposite effect. The combination of metformin and alendronate had a suppressive effect on both MSCs and fibroblasts differentiation. Treatment with metformin, alendronate, and their combination decreased serum concentrations of leptin and resistin in the chronic phase of arthritis. The histopathological examination showed that compared with the untreated CIOA group (OA score 9), the groups treated with metformin (OA score 4) or alendronate (OA score 6) had lower scores for cartilage changes. Metformin combined with alendronate significantly decreased the degree of cartilage degeneration (OA score 2), suggesting that this combination might be a useful approach for the treatment of OA patients.

Knee Osteoarthritis—How Close Are We to Disease-Modifying Treatment: Emphasis on Metabolic Type Knee Osteoarthritis

“…Interestingly, treatment with fenofibrate in in vitro experiments led to reduced proteoglycan loss and protected against cartilage degeneration induced by the administration of IL-1β. In our own study, a histological examination incorporating a mouse model of OA showed decreased cartilage degeneration after treatment with metformin, and the effect was more pronounced in the group treated with a combination of metformin and alendronate [ 32 ]. In patients with knee OA and accompanying obesity (BMI ≥ 30 kg/m 2 ; ≥2nd radiological grade according to Kellgren–Lawrence scale), metformin administration has been associated with slower cartilage volume loss in the medial compartment of the joint assessed via MRI after 4 years.…”

Repurposed and investigational disease-modifying drugs in osteoarthritis (DMOADs)

“… 101 , 102 Treatment with metformin increased antinociceptive activity, and anti-inflammatory and chondroprotective effects in OA mice with monosodium iodoacetate (MIA) model 103 as well as with collagenase-induced osteoarthritis (CIOA) model. 104 , 105 …”

“…101,102 Treatment with metformin increased antinociceptive activity, and anti-inflammatory and chondroprotective effects in OA mice with monosodium iodoacetate (MIA) model 103 as well as with collagenaseinduced osteoarthritis (CIOA) model. 104,105 A combination of metformin with COX-2 inhibitors (n = 968) reduced the risk of joint replacement surgery (12.81% versus 16.22%) over 10 years compared with COX-2 inhibitors alone (n = 1936) in type 2 DM patients with OA in a nationwide, retrospective, matched-cohort study. 106 However, data on the OA severity, disease duration and other assessment scores are unavailable, limiting the validity of study findings.…”

Can metformin relieve tibiofemoral cartilage volume loss and knee symptoms in overweight knee osteoarthritis patients? Study protocol for a randomized, double-blind, and placebo-controlled trial

“…Similar to this study, another study demonstrated that intraarticular injections of metformin in DMM-induced OA mice mitigated cartilage degradation by activating AMPK/the specifically silent information regulator 1 (SIRT1)-mediated autophagy [ 15 ]. Besides, the cartilage protective effect of metformin was also confirmed in both collagenase-induced and papain-induced OA mouse models [ 16 , 17 ]. Three other in vivo studies demonstrated that metformin also had an analgesic effect along with the joint structure-protective effects.…”