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Disease-Modifying Potential of Metformin and Alendronate in an Experimental Mouse Model of Osteoarthritis
Lyudmila Belenska-Todorova1, Sevdalina Nikolova Lambova2,3, Stela Stoyanova4
1Faculty of Medicine, Sofia University "St. Kliment Ohridski", 1407 Sofia, Bulgaria.
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.
Insights
Metformin and alendronate combination therapy shows promise in treating osteoarthritis (OA) in mice. This treatment reduced cartilage damage and key inflammatory markers, offering a potential new therapeutic strategy for OA patients.
Area of Science:
- Biomedical Science
- Pharmacology
- Rheumatology
Background:
- Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by cartilage damage, synovial inflammation, and pain.
- Current pharmacological treatments for OA yield unsatisfactory outcomes, necessitating the exploration of novel therapeutic approaches.
- Understanding the cellular and molecular mechanisms underlying OA progression is crucial for developing effective interventions.
Purpose of the Study:
- To investigate the therapeutic effects of metformin, alendronate, and their combination on the development and progression of collagenase-induced osteoarthritis (CIOA) in a mouse model.
- To evaluate the impact of these treatments on key cellular processes, inflammatory markers, and histopathological changes associated with OA.
Main Methods:
- Collagenase-induced osteoarthritis (CIOA) was established in female ICR mice.
- Mice were randomized into five groups: control, untreated CIOA, CIOA + metformin, CIOA + alendronate, and CIOA + metformin + alendronate.
- OA phenotype was assessed using flow cytometry, ELISA for adipokines (leptin, resistin), and histological analysis of knee joints.
Main Results:
- Metformin and alendronate, individually and in combination, inhibited RANK and RANKL expression on osteoblasts and osteoclasts.
- Metformin attenuated fibroblast differentiation, while alendronate affected mesenchymal stem cell (MSC) differentiation; the combination suppressed both.
- All treatments reduced serum leptin and resistin levels. Histopathology revealed significant reductions in cartilage degeneration scores with metformin (4), alendronate (6), and their combination (2) compared to untreated CIOA (9).
Conclusions:
- The combination of metformin and alendronate demonstrated a significant suppressive effect on cartilage degeneration in a mouse model of OA.
- These findings suggest that the combined administration of metformin and alendronate may represent a promising therapeutic strategy for managing osteoarthritis.
- Further research is warranted to translate these findings into clinical applications for OA patients.
