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An intra-articular salmon calcitonin-based nanocomplex reduces experimental inflammatory arthritis
Sinéad M Ryan1, Jason McMorrow, Anita Umerska
1Environmental Health Research Institute, School of Food Science and Environmental Health, Dublin Institute of Technology, Dublin 1, Cathal Brugha St., Ireland.
Abstract:
Prolonged inappropriate inflammatory responses contribute to the pathogenesis of rheumatoid arthritis (RA) and to aspects of osteoarthritis (OA). The orphan nuclear receptor, NR4A2, is a key regulator and potential biomarker for inflammation and represents a potentially valuable therapeutic target. Both salmon calcitonin (sCT) and hyaluronic acid (HA) attenuated activated mRNA expression of NR4A1, NR4A2, NR4A3, and matrix metalloproteinases (MMPs) 1, 3 and 13 in three human cell lines: SW1353 chondrocytes, U937 and THP-1 monocytes. Ad-mixtures of sCT and HA further down-regulated expression of NR4A2 compared to either agent alone at specific concentrations, hence the rationale for their formulation in nanocomplexes (NPs) using chitosan. The sCT released from NP stimulated cAMP production in human T47D breast cancer cells expressing sCT receptors. When NP were injected by the intra-articular (I.A.) route to the mouse knee during on-going inflammatory arthritis of the K/BxN serum transfer model, joint inflammation was reduced together with NR4A2 expression, and local bone architecture was preserved. These data highlight remarkable anti-inflammatory effects of sCT and HA at the level of reducing NR4A2 mRNA expression in vitro. Combining them in NP elicits anti-arthritic effects in vivo following I.A. delivery.
Insights
Salmon calcitonin (sCT) and hyaluronic acid (HA) reduce inflammation in arthritis models. Formulated in nanocomplexes (NPs), they target NR4A2, preserving joint structure and reducing inflammatory markers.
Area of Science:
- Biochemistry
- Immunology
- Pharmacology
Background:
- Rheumatoid arthritis (RA) and osteoarthritis (OA) pathogenesis involve prolonged inflammatory responses.
- The orphan nuclear receptor NR4A2 is a key regulator and potential biomarker for inflammation, representing a therapeutic target.
- Current treatments for inflammatory joint diseases have limitations, necessitating novel therapeutic strategies.
Purpose of the Study:
- To investigate the anti-inflammatory effects of salmon calcitonin (sCT) and hyaluronic acid (HA) on NR4A2 expression in vitro and in vivo.
- To evaluate the efficacy of sCT and HA formulated in chitosan-based nanocomplexes (NPs) for treating inflammatory arthritis.
- To assess the therapeutic potential of targeting NR4A2 in the context of joint inflammation.
Main Methods:
- Human chondrocyte (SW1353) and monocyte (U937, THP-1) cell lines were treated with sCT and HA to assess NR4A2 mRNA expression.
- sCT and HA were formulated into chitosan-based NPs, and sCT release and biological activity were confirmed.
- The K/BxN serum transfer-induced inflammatory arthritis model in mice was used to evaluate the in vivo efficacy of NP treatment via intra-articular (I.A.) injection.
Main Results:
- Both sCT and HA individually attenuated the mRNA expression of NR4A1, NR4A2, NR4A3, and matrix metalloproteinases (MMPs) in human cell lines.
- Combined sCT and HA in NPs demonstrated synergistic down-regulation of NR4A2 expression compared to individual agents.
- Intra-articular administration of sCT/HA NPs in arthritic mice significantly reduced joint inflammation, NR4A2 expression, and preserved local bone architecture.
Conclusions:
- sCT and HA exhibit significant anti-inflammatory effects by reducing NR4A2 mRNA expression in vitro.
- Formulation of sCT and HA into NPs enhances their anti-inflammatory potential and therapeutic efficacy in an in vivo model of inflammatory arthritis.
- Targeting NR4A2 with sCT and HA delivered via NPs represents a promising therapeutic strategy for inflammatory joint diseases like RA and OA.
