Abstract
ObjectiveSalmon calcitonin has chondroprotective effect both in vitro and in vivo, and is therefore being tested as a candidate drug for cartilage degenerative diseases. Recent studies have indicated that different chondrocyte phenotypes may express the calcitonin receptor (CTR) differentially. We tested for the presence of the CTR in chondrocytes from tri-iodothyronin (T3)-induced bovine articular cartilage explants. Moreover, investigated the effects of human and salmon calcitonin on the explants.MethodsEarly chondrocyte hypertrophy was induced in bovine articular cartilage explants by stimulation over four days with 20 ng/mL T3. The degree of hypertrophy was investigated by molecular markers of hypertrophy (ALP, IHH, COLX and MMP13), by biochemical markers of cartilage turnover (C2M, P2NP and AGNxII) and histology. The expression of the CTR was detected by qPCR and immunohistochemistry. T3-induced explants were treated with salmon or human calcitonin. Calcitonin down-stream signaling was measured by levels of cAMP, and by the molecular markers.ResultsCompared with untreated control explants, T3 induction increased expression of the hypertrophic markers (p<0.05), of cartilage turnover (p<0.05), and of CTR (p<0.01). Salmon, but not human, calcitonin induced cAMP release (p<0.001). Salmon calcitonin also inhibited expression of markers of hypertrophy and cartilage turnover (p<0.05).ConclusionsT3 induced early hypertrophy of chondrocytes, which showed an elevated expression of the CTR and was thus a target for salmon calcitonin. Molecular marker levels indicated salmon, but not human, calcitonin protected the cartilage from hypertrophy. These results confirm that salmon calcitonin is able to modulate the CTR and thus have chondroprotective effects.
Highlights
The pathogenesis of cartilage loss in joint degenerative diseases is not fully understood, but experimental and clinical studies have shown that abnormal subchondral bone turnover and cartilage calcification affects the integrity of the articular cartilage structure [1,2,3]
T3 induced early hypertrophy of chondrocytes, which showed an elevated expression of the calcitonin receptor (CTR) and was a target for salmon calcitonin
These results confirm that salmon calcitonin is able to modulate the CTR and have chondroprotective effects
Summary
The pathogenesis of cartilage loss in joint degenerative diseases is not fully understood, but experimental and clinical studies have shown that abnormal subchondral bone turnover and cartilage calcification affects the integrity of the articular cartilage structure [1,2,3]. Because of the strong inter-relationship between cartilage and subchondral bone, an ideal agent for joint degenerative diseases would have positive effects on both remodeling subchondral bone and the prevention or regeneration of articular cartilage. Calcitonin is a part of the calcitonin family consisting of calcitonin (CT), a-calcitonin gene-related peptide (a-CGRP), bCGRP, adrenomodullin (AM), and amylin [7]. In mammals, these peptides signal through two closely related type II GPCRs (Calcitonin Receptor and Calcitonin Receptor-like Receptor) and three unique receptor activity-modifying proteins (RAMPs) [8]. Human CT, salmon CT, and amylin share receptors [10]; what separates salmon CT from human CT is an intrinsic ability to bind to and activate the CTR in the presence of RAMPs, most notably in the confirmation normally activated potently by Amylin [11,12]
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