Thus, the abnormalities of energy metabolism and oxidative stress observed in our PINK1 mutant patient cells will have a deleterious synergy with the parallel impairment of mitophagy, leading to the accumulation of defective mitochondria with the consequent impairment of ATP synthesis and increased free radical production. Such effects are likely to contribute to dopaminergic neuronal cell dysfunction and death. Fibroblast and neuronal cells are known to differ in their regulation of calcium homeostasis and in the role of mitochondria in calcium buffering. Importantly, using artificial calcium stimulation in fibroblasts, we found that this induced opening of the PTP in cells with pathological mutations. Our experimental conditions have therefore allowed us to demonstrate a defect in mitochondrial calcium regulation in these mutant cells that cannot be visualized with physiological stimulation. Bone tissue continuously undergoes remodeling through mechanical coupling of osteoclastic bone resorption and osteoblastic bone formation. Bone homeostasis is controlled by a variety of soluble factors such as growth factors, hormones, and cytokines. For example, insulin-like growth factor, transforming growth factor and parathyroid hormone stimulate the production of bone collagen and matrix proteins in osteoblasts and increase osteoclast apoptosis, thus resulting in increased bone formation. Moreover, OCN modulates the expression of adiponectin and leptin in adipocytes,suggesting that it may control an intimate link between bone and fat. Recent findings that OCN expression is associated Hypaconitine positively with insulin sensitivity, as well as the observation that decreased bone density and increased fracture risk are closely associated with diabetes, strongly support the notion that bone homeostasis is affected by insulin insufficiency or resistance under diabetic conditions. Consistently, hyperglycemic and hyperleptinemic conditions are identified as osteoporotic risk factors. However, the molecular links between these risk factors and osteoporosis remain largely uncharacterized. In this study, we observed that TH mice, a polygenic diabetes model, displayed severe osteoporotic phenotypes with male predominance and intended to uncover the molecular links between inflammatory factors and osteoporosis in TH mice. Whereas bone mineral density and OCN were significantly decreased in Mesaconitine, RANKL, IL-6, and IL-17 expression and osteoclast activity were considerably elevated. In addition, we observed that RANKL expression was increased in CD4+ T cells of TH mice and that blockade of IFN-c and leptin further increased IL-17 production in CD4+ T cells. These results suggest that TH mice displaying bone loss as well as increased levels of IL-17 and RANKL in T cells due to hyperleptinemia may be an effective animal model for osteoporosis secondary to diabetes in males. TH mice have been characterized by hyperleptinemia, hyperinsulemia, hyperlipidemia and male-specific hyperglycemia, and they are established as a polygenic model for type II diabetes with obesity. Insulin deficiency or resistance as well as hyperglycemia in patients with diabetes are known risk factors for metabolic bone diseases, including osteoporosis. Both leptin-deficient ob/ob mice and leptin receptor-deficient db/db mice reveal increased adiposity together with decreased BMD, suggesting an association between adiposity and aberrant BMD. Moreover, T cell inflammation in the adipose tissue of these obese mice reveal increased levels of TNF-a, IFNc, or IL-6, resulting in dysregulation of bone homeostasis. Our results also demonstrate that male TH mice with hyperglycemia and obesity underwent reduction of BMD due to increased T cell inflammation. Although both female and male TH mice are accompanied by obesity and diminished locomotor activity, bone loss was specific to male TH mice.