Abstract
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, PPARβ/δ 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 PPARβ/δ 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 PPARβ/δ agonists. In vitro experiments suggested that PPARβ/δ 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 PPARβ/δ to regulate macrophage polarization. In conclusion, our study demonstrates the potential of PPARβ/δ agonist as a therapeutic target for the treatment of osteoporosis and immune homeostasis disorder in diabetic patients.
Highlights
Diabetes mellitus, a systemic metabolic disorder syndrome, is usually accompanied by hyperglycemia and chronic tissue and organ damage
Through tartrate-resistant acid phosphatase (TRAP) staining, we found that osteoclast activity in DM group was significantly increased, and PPARβ/δ agonist treatment could reduce the activation of osteoclasts under diabetic condition (Figures 2B,C)
Given that immune homeostasis imbalance was an important factor leading to diabetic complications, we explored the effect of PPARβ/δ agonist one the ROS level and pro-inflammatory polarization of macrophages induced by high glucose
Summary
A systemic metabolic disorder syndrome, is usually accompanied by hyperglycemia and chronic tissue and organ damage. The imbalance of immune homeostasis is one of the main characteristics of diabetic complications. Diabetes mellitus can lead to increased inflammatory infiltration, pro-inflammatory mediators including TNF-α, IL-1β, IL-6 and IL-18, resulting in aggravated inflammatory response (Graves and Kayal, 2008). ROS production in macrophages increases under high glucose culture, resulting in abnormal macrophage polarization and disordered immune response (Rendra et al, 2019). Skeletal syndrome is an important complication of diabetic patients, including osteoporosis, increased fracture risk, and impaired bone healing properties. Current evidence suggested that diabetic status could stimulate osteoclast differentiation and bone resorption (Jiao et al, 2015). The circulating levels of tartrate-resistant acid phosphatase (TRAP) increased, which indicated the enhanced osteoclast activity (Suzuki et al, 2005). During the fracture healing process, diabetic rats showed increased
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