Overexpression of SENP3 promotes PPAR-? transcription through the increase of HIF-1a stability via SUMO2/3 and participates in molecular mechanisms of osteoporosis

Patients with type II diabetes are exposed to a high risk of osteoporosis. The present study sought to exploit the detailed mechanisms of the SENP3/HIF-1a/PPAR-? axis in osteoporosis. A rat model of type II diabetic osteoporosis was established, followed by the isolation of bone marrow mononuclear macrophages (BMMs). Gain- and loss-of-function assays were conducted in rat models and BMMs from rat models, followed by the evaluation of SENP3, HIF-1a, and PPAR-? expression and detection of osteoclast differentiation-related indexes. Next, the SUMOylated modification of HIF-1a and the regulation of SENP3 on SUMOylated modification level of HIF-1a were assessed using immunoprecipitation, and the binding of HIF-1a to the PPAR? promoter was identified with ChIP and dual-luciferase reporter assays. SENP3 and HIF-1a expression was down-regulated in tissues of type II diabetes-induced osteoporotic rats and BMMs, with high SUMOylated modification levels of HIF-1a. Mechanically, HIF-1a was modified by SUMO2/3. SENP3 suppressed SUMOylated modification of HIF-1a and enhanced HIF-1a stability. HIF-1a bound to the PPAR-? promoter and facilitated PPAR-? transcription. SENP3 overexpression restrained osteoblast differentiation in type II diabetes-induced osteoporotic rats and BMMs from rat models. SENP3 knockdown facilitated osteoclast differentiation in type II diabetes-induced osteoporotic rats and BMMs from rat models, which was neutralized by further HIF-1a overexpression. To sum up, SENP3 overexpression restrained osteoclast differentiation in type II diabetic osteoporosis by increasing HIF-1a stability and expression and thus promoting PPAR-? expression via de-SUMOylation, which might expand the understanding of the mechanisms of type II diabetes combined with osteoporosis.