Abstract
We report dual therapeutic effects of a synthetic heparin-binding peptide (HBP) corresponding to residues 15–24 of the heparin binding site in BMP4 in a collagen-induced rheumatic arthritis model (CIA) for the first time. The cell penetrating capacity of HBP led to improved cartilage recovery and anti-inflammatory effects via down-regulation of the iNOS-IFNγ-IL6 signaling pathway in inflamed RAW264.7 cells. Both arthritis and paw swelling scores were significantly improved following HBP injection into CIA model mice. Anti-rheumatic effects were accelerated upon combined treatment with Enbrel® and HBP. Serum IFNγ and IL6 concentrations were markedly reduced following intraperitoneal HBP injection in CIA mice. The anti-rheumatic effects of HBP in mice were similar to those of Enbrel®. Furthermore, the combination of Enbrel® and HBP induced similar anti-rheumatic and anti-inflammatory effects as Enbrel®. We further investigated the effect of HBP on damaged chondrocytes in CIA mice. Regenerative capacity of HBP was confirmed based on increased expression of chondrocyte biomarker genes, including aggrecan, collagen type II and TNFα, in adult human knee chondrocytes. These findings collectively support the utility of our cell-permeable bifunctional HBP with anti-inflammatory and chondrogenic properties as a potential source of therapeutic agents for degenerative inflammatory diseases.
Highlights
Rheumatic arthritis (RA) is one of the most common autoimmune rheumatic diseases (AIRD) caused by dysregulation of tolerance to self-antigens, leading to chronic systemic inflammatory disorders involving the musculoskeletal system [1]
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We initially examined the efficacy of the BMP-4-derived HBP against RA and whether the peptide could reduce the side-effects of Enbrel®, with a view to assessing its utility as a candidate or alternative agent for RA therapy
Summary
Rheumatic arthritis (RA) is one of the most common autoimmune rheumatic diseases (AIRD) caused by dysregulation of tolerance to self-antigens, leading to chronic systemic inflammatory disorders involving the musculoskeletal system [1]. In randomized controlled clinical trials, these drugs are reported to be effective in recovery of inflammation-related clinical signs in RA patients with response failure to synthetic DMARDs [7]. Other FDA-approved drugs for treatment of moderate to severe RA include abatacept, rituximab, and tocilizumab. These drugs commonly induce severe side-effects, such as osteoporosis, liver function failure, and even lymphoma, due to the complexity of the inflammatory network [8,9]. Treatment with synthetic disease-modifying anti-rheumatic drugs (DMARD), including methotrexate, sulfasalazine, and leflunomide, represents an important paradigm shift that can lead to remarkable improvement of clinical symptoms and delayed joint damage. Despite the effectiveness of these medications, a significant number of RA patients continue to experience clinical symptoms of inflammation and progressive joint destruction, clearly suggesting that therapeutic blockade with any one cytokine is not necessarily sufficient for relief of RA [11,12]
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