PPAR beta/delta Agonist Alleviates Diabetic Osteoporosis via Regulating M1/M2 Macrophage Polarization

Diabetic osteoporosis is a common complication in diabetic patients, leading to increased fracture risk and impaired bone healing. As a member of the peroxisome proliferator-activated receptor (PPAR) family, PPAR beta/delta agonist is suggested as a therapeutic target for the treatment of metabolic syndrome, and has been reported to positively regulate bone turnover by improving osteogenesis. However, its regulatory role in diabetic osteoporosis has not been reported yet. Here, we explored the therapeutic effects and potential mechanisms of PPAR beta/delta agonist to the osteoporotic phenotypes of diabetic mice. Our results indicated that the osteoporotic phenotypes could be significantly ameliorated in diabetic mice by the administration of PPAR beta/delta agonists. In vitro experiments suggested that PPAR beta/delta agonist treatment could alleviate the abnormal increase of osteoclast activity in diabetic mice by rectifying high glucose-mediated macrophage dysfunction instead of directly inhibiting osteoclast differentiation. Mechanistically, Angptl4 may act as a downstream target of PPAR beta/delta to regulate macrophage polarization. In conclusion, our study demonstrates the potential of PPAR beta/delta agonist as a therapeutic target for the treatment of osteoporosis and immune homeostasis disorder in diabetic patients.