What is it about?
Rheumatoid arthritis in an inflammatory disease characterised by chronic damage and pain, in the joint. Herein, inflammation causes damage to bones and cartilage, the tissue allowing for frictionless movement of the joint, leading to severe pain and loss of joint mobility. Current treatments are somewhat effective to manage the symptoms of joint disease however many patients do not respond to treatment, and none of the current drugs can repair the destruction caused to the joint tissues. Accordingly, there is an urgent clinical need for novel therapeutic approaches. While screening for candidate tissue-protective molecules to develop as potential treatments for arthritis, we discovered a molecule called alpha-1-antitrypsin (AAT): AAT possesses anti-inflammatory and cartilage-protective properties in a mouse model of arthritis. In this study, we expand on these findings and dissect the properties of AAT in the context of cartilage protection, joint inflammation and associated pain. We discovered that AAT injected directly in the joint as well as systemically, reverses joint inflammation, pain and stopped cartilage degradation in distinct and complementary models of experimental arthritis. Of interest, we elucidated at least partly that the biological effects of AAT were consequent to new cartilage formation – the result of AAT-mediated activation of molecular switches inside the cartilage cells. These new data prompt us to propose that AAT could be modelled for new therapeutic strategies to reduce arthritic pain and inflammation and repair/restore compromised cartilage functions.
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Why is it important?
alpha-1-antitrypsin has been used since 1988 with an excellent safety record in human patients who congenitally lack this protease inhibitor and develop lung disease. Further work, which we are currently conducting, to fully assess the role of alpha-1-antitrypsin in the human joint, could potentially fast-track its repurposing as an alternative, safe treatment for arthritis - one that provides both structural and functional improvements to patients joints.
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This page is a summary of: Alpha‐1‐antitrypsin reduces inflammation and exerts chondroprotection in arthritis, The FASEB Journal, March 2021, Wiley,
DOI: 10.1096/fj.202001801r.
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Identification of Novel Chondroprotective Mediators in Resolving Inflammatory Exudates
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Self Help for Arthritis
Persistent inflammation with inadequate tissue repair is characteristic of rheumatoid arthritis (RA) and osteoarthritis (OA), but currently available treatment options rely heavily on pain management rather than strategies to repair cartilage defects. As recent studies have identified endogenous molecules, such as melanocortins, that can limit chondrocyte inflammation and cartilage degradation, Kaneva et al. (p. 2876) sought to identify additional endogenous molecules that may aid in resolution of joint inflammation and limit cartilage destruction. Using lung exudate from rats with pleurisy, chondrocytes stimulated with inflammatory exudate (collected 6 h after pleurisy induction) displayed typical catabolic activity as evidenced by decreased COL2A1 and ACAN and increased MMP13 mRNA expression. Resolving exudate (collected 24 h after pleurisy induction) was mostly inactive when added to chondrocytes alone, but stimulation of chondrocytes with both the resolving and the inflammatory exudate reduced MMP13 transcription by 20% and increased ACAN and COL2A1 transcription. Following gel filtration chromatography and proteomics analysis of the exudates, the authors selected three acute phase proteins, α1-antitrypsin (AAT), hemopexin (HX), and gelsolin (GSN), that were further analyzed for their possible relevance to chondroprotection. When added to chondrocytes stimulated with IL-1β, AAT and GSN improved COL2A1 and ACAN expression and reduced MMP13 expression, whereas HX was only effective at diminishing MMP13 expression. Addition of AAT, GSN, or HX to high-density 3D micromass cultures of chondrocytes reversed the effects of both IL-1β and osteoarthritis synovial fluid on IL-6, IL-8, and MMP-13 release and increased sulfated glycosaminoglycan deposition, which is an indication of improved cartilage health. Finally, when compared with untreated contralateral controls, intra-articular injection of GSN or AAT protected joint cartilage from erosion in mice with serum-induced inflammatory arthritis. This study identifies three proteins in resolving exudates that may be potential leads for drug discovery programs and demonstrates that anti-arthritic strategies may benefit from the exploitation of endogenous pathways that mediate the resolution of inflammation.
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