An intra-articular salmon calcitonin-based nanocomplex reduces experimental inflammatory arthritis

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.

Identification of Novel Chondroprotective Mediators in Resolving Inflammatory Exudates

“…The serum-transfer model of inflammatory arthritis has been applied to unveil chondroprotective mechanisms as evoked by extracellular vesicles (22) or calcitonin nanomedicines (23,24). GSN or AAT were administered by i.a.…”

Self-Assembled Hyaluronate/Protamine Polyelectrolyte Nanoplexes: Synthesis, Stability, Biocompatibility and Potential Use as Peptide Carriers

“…16 A total of 5 ml of sample was placed in the sample reservoir (donor phase) of the centrifugal filter device and centrifuged for 1 hour at 4,537 g (3,000 rpm). After centrifugation, the volume of the solution in the filtrate vial (acceptor phase) was measured, and the filtrate was assayed for sCT content via HPLC, as described below.…”

“…15 We recently presented studies on the optimum formation condition and properties of crosslinker-and surfactant-free HA/chitosan NPs 4 and also showed that salmon calcitonin/ HA/chitosan NPs were able to reduce experimental inflammatory arthritis. 16 Because HA and sCT produced important anti-inflammatory effects in vitro, 16 an HA-based delivery system appears to be a particularly suitable carrier for sCT. Calcitonin is currently recommended for shortterm use in Paget's disease, acute bone loss due to sudden immobilization and hypercalcaemia caused by cancer.…”

Drugs and Polymers for Delivery Systems in OA Joints: Clinical Needs and Opportunities

“…However, reproducibility is low and they often have a high immunogenicity [68]. Natural polymers investigated for IA drug delivery include Chitosan which was shown to be able to incorporate Cxb or Flurbiprofen and extend their residence time in the joint [28,41,70], Diclofenac Sodium loaded albumin microspheres provided a significant reduction of arthritis after 30 days of incubation in a rabbit knee [38], gelatin microspheres are able to incorporate different NSAIDs or proteins, and Saravanan et al found gelatin microspheres to be more stable than albumin, but residence times are still relatively short [30,33,71].…”