Background/Purpose: A decline of mitochondrial function has been described in OA chondrocytes and RA synoviocytes. Recent ex vivo findings support a connection between mitochondrial dysfunction and activation of inflammatory and destructive pathways in these cells. The aim of this study was to investigate in an in vivo articular model if the intraarticular injection of oligomycin, an inhibitor of mitochondrial function, induces a destructive and inflammatory response in rat knee joints.

Methods: 24 female wistar rats (180-220g) were divided into three study groups: Healthy (no intraarticular injection); Lipopolysaccharide (LPS)-treated, positive control (left joint injected with: LPS 10mg and right joint with vehicle); and Oligomycin (OLI)-treated (left joint injected with Oligomycin 20mg and right joint with vehicle). Three intraarticular injections were carried out at 0, 2 and 5 days. Rats were sacrificed at day 6, hind paws were collected and joint tissues were obtained. Measurement of joint diameters on stimulis- and control-injected paws was performed at days 0 and 6. Histopathologic lesions were evaluated by hematoxilyn-eosin (H&E) and masson trichromic stain sections in synovial tissue and by safranin O staining in cartilage. ROS production by dihydroethidium (DHE) staining was evaluated. By RT-PCR, CINC-1, IL-1b, CCL-2 and TNF-a  gene expression was analyzed in extracted cartilage. And by immunohistochemical staining, IL-8, equivalent of CINC-1, expression was localized in the joint tissue.

Results: OLI-treated hind paws significantly increased the joint diameter (0.9±0.1 mm, n=8, p<0.05, vs vehicle-injected joints), similarly to LPS-treated (2±0.3 mm, n=8, p<0.05, vs vehicle-injected joints). In relation, histological evaluation of synovial tissue by H&E staining revealed that joints treated with mitochondrial inhibitor present greater synovial lining hyperplasia, proliferation of subsynovial tissue and infiltration of a marked number of inflammatory cells while the right control synovial only contained a moderate synovial proliferation and inflammation (3.3±0.1 vs. 2.1±0.2, respectively, n=8, p<0.001, vs vehicle-injected joints).  Besides, a higher increment in ROS production was detected in synovial tissue from OLI-injected knees than observed in vehicle-injected counterparts. Immunohistochemical studies on IL-8 also showed a greater expression in synovial tissue from OLI-injected joints versus those from vehicle-injected joints, coinciding with a strong neutrophils infiltration. In relation to cartilage, when the loss of matrix in this tissue by safranin O staining was evaluated no differences were observed. We also failed to detect modulations in IL-8 immunoperoxidase staining in cartilage. By contrast, when CINC-1 mRNA expression was analyzed in this tissue, a significant increment in OLI-injected joints was detected (n=8, p<0.05 vs. vehicle-injected joint), similar to those LPS-treated.

Conclusion: The data seems to support that a loss of mitochondrial function in the joint could participate in rheumatoid pathology through generating an inflammatory response in the articular tissue, contributing to the perpetuation of joint injury.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-intraarticular-injection-of-an-inhibitor-of-complex-v-of-mitochondrial-respiratory-chain-induces-a-pathological-response-in-rat-knee-joints/