Rilmenidine protects against joint damage in MIA-induced model of osteoarthritis in rats Purpose: Osteoarthritis is a common problem, and its incidence significantly increases with age. Patients suffer from excruciating pain while moving, and currently, major treatment options consist of surgery. Rilmenidine is a potent antihypertensive agent with a high affinity for imidazoline and alpha2 adrenergic receptors. Based on the knowledge that these receptors are also related to bone turnover and pain, we aimed to reveal the effect of rilmenidine on the osteoarthritis model in rats. Methods: Monosodium iodoacetate(MIA) was used to induce osteoarthritis. Animals were treated with rilmenidine(0.5, 2 mg/kg) for 14 days. Hot plate test was performed to assess pain response before and end of the drug treatments, in addition to the walking track analysis. Twenty-four hours after the last drug treatment, serum levels of receptor activator of nuclear factor kappa-Β ligand(RANKL) and osteoprotegerin(OPG) were measured. Hematoxylin&eosin and safranin-O staining were used to evaluate MIA and rilmenidine induced changes in the hindlimb joints. Results: Our results demonstrated that rilmenidine(2 mg/kg) prevented MIA-induced thermal hyperalgesia with improved walking behavior in the walking track test. Additionally, rilmenidine(2 mg/kg) also prevented MIA-induced increase in the RANKL and OPG levels in the serum. Histopathological analysis showed that rilmenidine was protective on joint capsule and matrix. Conclusion: Our results suggest that rilmenidine showed the antinociceptive effect on MIA-induced OA via improving bone turnover.

Mitochondria-rich brown adipocytes dissipate cellular fuel as heat by thermogenic energy expenditure (TEE). Prolonged nutrient excess or cold exposure impair TEE and contribute to the pathogenesis of obesity, but the mechanisms remain incompletely understood. Here we report that stress-induced proton leak into the matrix interface of mitochondrial innermembrane (IM) mobilizes a group of proteins from IM into matrix, which in turn alter mitochondrial bioenergetics. We further determine a smaller subset that correlates with obesity in human subcutaneous adipose tissue. We go on to show that the top factor on this short list, acyl-CoA thioesterase 9 (ACOT9), migrates from the IM into the matrix upon stress where it enzymatically deactivates and prevents the utilization of acetyl-CoA in TEE. The loss of ACOT9 protects mice against the complications of obesity by maintaining unobstructed TEE. Overall, our results introduce aberrant protein translocation as a strategy to identify pathogenic factors.