Development of a new hyaluronic acid-calcitonin conjugate for the local treatment of osteoarthritis

  • Campisi M
  • Galesso D
  • Mero A
  • et al.
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Abstract

Purpose: Salmon calcitonin (sCT) has been shown to exert beneficial metabolic actions on cartilage and bone turnover and may therefore be useful in the management of osteoarthritis (OA). A calcitonin-based oral treatment for knee OA recently failed to meet the primary endpoint for efficacy in a two-year placebo-controlled clinical trial, though demonstrating positive effects on pain and function. The objective of our project is to synthesize a new polymeric conjugate between hyaluronic acid (HA) and salmon calcitonin and to evaluate its potential as intraarticular treatment for OA. The rationale is to retain sCT in the joint cavity, thus maximizing and prolonging the local activity and avoiding the side effects related to a systemic administration. Methods: HA was linked to sCT by means of a spacer having pendant aldehyde groups for selective conjugation at the N-terminus of the peptide. The residual activity of conjugated sCT was investigated in rats by measuring the plasma calcium level after i.v. injection. Preliminary PK studies were performed by labeling HA-sCT and sCT with a fluorescent dye for the detection in blood samples after i.a. injection. In addition, blood samples were withdrawn at fixed times up to 24 hours and the total calcium levels were measured using a colorimetric calcium assay. Unilateral OA was surgically induced in the rabbit knees by anterior cruciate ligament transection (ACLT). Controls (PBS and HA), sCT and HA-sCT at 25, 100 and 400 UI, were administered by i.a. injection once a week at day 10, 17 and 24 post-surgery. The efficacy was evaluated by macroscopic examination of the treated joint, histopathological assessment of the synovial membrane and of the femoral condyles. The histopathological criteria score was based on the evaluation of four parameters: articular cartilage morphology, subchondral bone morphology, cartilage thickness, and arrangement of chondrocytes. Results: The new HA-sCT conjugate was synthesized according to a patented technology that avoids the formation of heterogeneous and cross-linked products. The potency of the conjugated sCT was evaluated by i.v. injection, showing that it maintains a comparable potency with respect to the free protein and sustains the hypocalcaemic action for a longer time. Interestingly, after local administration, unlike free sCT, HA-sCT did not cause a systemic reduction of calcium concentration, suggesting a negligible extra-articular diffusion of the conjugated peptide. The PK study with labelled sCT confirmed this encouraging result: while i.a. injection of HA-sCT led to very low and constant plasma peptide concentration, the local administration of free sCT resulted in high fluorescence in plasma, demonstrating a fast clearance of the peptide from the knee joint cavity, in agreement with the previously observed hypocalcaemic effect after i.a. injection. The efficacy of the HA-sCT treatment was tested in a rabbit OA model, where a chondroprotective effect of the highest dose tested was proven by macro- and microscopic assessments and histological findings. The cartilage surfaces of the weight-bearing parts, such as the medial tibial plateau and the lateral and medial femoral condyle, were evaluated and graded for degradation severity The average scores on the macroscopic assessment of sCT or HA-sCT treated group indicated a significant reduction in cartilage damage in comparison to controls. PAS staining of nuclei, indicating the maintenance of chondrocyte number, and Alcian blue staining of proteoglycan, indicating the matrix integrity of the cartilage, were significantly positive in the majority of the HA-sCT treated groups. Conclusions: The in vivo PK and efficacy/safety profiles of sCT and HAsCT were examined in this study in view of a potential application in the treatment of OA. Although the i.a. injection of the different sCT-based formulations showed to be comparably chondroprotective in a mechanical model of OA in vivo, the HA-peptide conjugate has the advantage of a sustained action and of a decrease in systemic exposure to sCT with consequent potential safety concerns. The promising results encourage further development and investigation on this therapeutic approach for OA. (Table presented).

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Campisi, M., Galesso, D., Mero, A., & Pasut, G. (2014). Development of a new hyaluronic acid-calcitonin conjugate for the local treatment of osteoarthritis. Osteoarthritis and Cartilage, 22, S475–S476. https://doi.org/10.1016/j.joca.2014.02.903

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