dorsomorphin and Osteoarthritis

Cartilage calcification contributes to the development and progression of osteoarthritis (OA). It has been well-investigated adiponectin regulates vascular calcification. The purpose of this study is to investigate the therapeutic value and the molecular mechanism of AdipoRon, an adiponectin receptor agonist, on the chondrocytes calcification. Primary chondrocytes were isolated and cultured from normal cartilage and OA cartilage. The calcification in tissues was evaluated by inductively coupled plasma/atomic emission spectroscopy and alizarin red S staining. The calcification in chondrocytes was determined using the alkaline phosphatase (ALP) staining and an ALP assay kit. The cellular effects of AdipoRon were assessed by immunofluorescence staining and Western blot analysis. We found that calcification was significantly increased in OA cartilage tissues and cells. Importantly, the degree of calcification and ALP activity of the OA chondrocytes was decreased upon the treatment with AdipoRon. The AdipoRon-induced cellular effects, including the reduction of the calcification of chondrocytes and improvement of autophagy, were blocked by dorsomorphin, an 5'-adenosine monophosphate-activated protein kinase (AMPK) inhibitor. Moreover, autophagy activation by AdipoRon was mediated by the AMPK-mammalian target of rapamycin (mTOR) signaling pathway. Our results suggest that AdipoRon significantly alleviates the calcification of OA chondrocytes via activating AMPK-mTOR signaling to promote autophagy. Therefore, AdipoRon could be a potential therapeutic agent for the prevention and treatment of OA.

Topics: Adiponectin; Adolescent; Adult; Aged; AMP-Activated Protein Kinases; Apoptosis; Autophagy; Calcification, Physiologic; Cartilage; Cartilage, Articular; Chondrocytes; Female; Humans; Knee; Male; Microscopy, Fluorescence; Osteoarthritis; Piperidines; Pyrazoles; Pyrimidines; Receptors, Adiponectin; Signal Transduction; TOR Serine-Threonine Kinases; Young Adult

Osteoarthritis is the most common degenerative joint disease and causes major pain and disability in adults. It has been reported that mitochondrial dysfunction in chondrocytes was associated with osteoarthritis. Puerarin has multiple effects including restoring mitochondrial function. In this study, the potential effects of puerarin on osteoarthritis and osteoarthritis associated mitochondrial dysfunctions were evaluated.. Osteoarthritis rats were treated with puerarin and the severity of osteoarthritis and cartilage damages was evaluated. The mitochondrial biogenesis and functions were analyzed by measuring related proteins expression, mitochondrial DNA content, ATP production, and oxygen consumption. The dependence of AMP-activated protein kinase (AMPK) pathway on puerarin-regulated mitochondrial function was analyzed by applying AMPK inhibitor Compound C.. Puerarin treatment alleviated mechanical hyperalgesia and cartilage damage in osteoarthritis rats. Puerarin increased mitochondrial biogenesis and attenuated mitochondrial dysfunctions in osteoarthritis rats. AMPK inhibitor Compound C abolished puerarin's effects.. Puerarin attenuates osteoarthritis by upregulating the AMPK/proliferator-activated receptor-γ coactivator signaling pathway in osteoarthritis rats.

Topics: AMP-Activated Protein Kinases; Animals; Cartilage, Articular; Cells, Cultured; Drug Interactions; Hyperalgesia; Isoflavones; Male; Mitochondria; Osteoarthritis; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphorylation; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Random Allocation; Rats; Rats, Sprague-Dawley; Signal Transduction; Up-Regulation; Vasodilator Agents