PPARβ/δ Agonist Alleviates Diabetic Osteoporosis via Regulating M1/M2 Macrophage Polarization

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.

Medium-chain fatty acids modify macrophage expression of metabolic and inflammatory genes in a PPAR β/δ-dependent manner

“…This is not necessarily a pro-inflammatory action, as COX-2 catalyzes a common step in the synthesis of both pro- and anti-inflammatory eicosanoids 33 . The mediation of PPAR β/δ in this effect of MCFA is in line with prior experiments showing that PPAR β/δ is important for the polarization of macrophages towards the anti-inflammatory M2 phenotype, characterized by reduced activity of the NF-kB pathway 34 .…”

Medium-chain fatty acids affect the expression of metabolic and inflammatory genes in macrophages: mediation by PPAR β/δ

“…This is not necessarily a pro-in ammatory action, as COX-2 catalyzes a common step in the synthesis of both pro-and anti-in ammatory eicosanoids (30). The mediation of PPAR b/d in this effect of MCFA is in line with prior experiments showing that PPAR b/d is important for the polarization of macrophages towards the anti-in ammatory M2 phenotype, characterized by reduced activity of the NF-kB pathway (31).…”

Efferocytosis: An Emerging Therapeutic Strategy for Type 2 Diabetes Mellitus and Diabetes Complications

“…Osteoporosis is a common disease in elderly people, with osteoporosis caused by T2DM considered the most detrimental. 144 Experiments in mice models have revealed that the PPARβ/δ agonist 145 and exendin-4 synergized with vitamin D 146 aid in the improvement of diabetic osteoporosis due to the correction of macrophage dysfunction via facilitating M1/M2 macrophage polarization. Co-culture of osteoclasts (OCs) and neutrophils in the HG environment revealed an increase in apoptotic neutrophils and a loss of efferocytosis of OCs, which could be reversed by an efferocytosis activator such as lipoxin A4 and insulin.…”