Abstract
BackgroundCalcitonin has been demonstrated to have chondroprotective effects under pre-clinical settings. It is debated whether this effect is mediated through subchondral-bone, directly on cartilage or both in combination. We investigated possible direct effects of salmon calcitonin on proteoglycans and collagen-type-II synthesis in osteoarthritic (OA) cartilage.MethodsHuman OA cartilage explants were cultured with salmon calcitonin [100 pM-100 nM]. Direct effects of calcitonin on articular cartilage were evaluated by 1) measurement of proteoglycan synthesis by incorporation of radioactive labeled 35SO4 [5 μCi] 2) quantification of collagen-type-II formation by pro-peptides of collagen type II (PIINP) ELISA, 3) QPCR expression of the calcitonin receptor in OA chondrocytes using four individual primer pairs, 4) activation of the cAMP signaling pathway by EIA and, 5) investigations of metabolic activity by AlamarBlue.ResultsQPCR analysis and subsequent sequencing confirmed expression of the calcitonin receptor in human chondrocytes. All doses of salmon calcitonin significantly elevated cAMP levels (P < 0.01 and P < 0.001). Calcitonin significantly and concentration-dependently [100 pM-100 nM] induced proteoglycan synthesis measured by radioactive 35SO4 incorporation, with a 96% maximal induction at 10 nM (P < 0.001) corresponding to an 80% induction of 100 ng/ml IGF, (P < 0.05). In alignment with calcitonin treatments [100 pM-100 nM] resulted in 35% (P < 0.01) increased PIINP levels.ConclusionCalcitonin treatment increased proteoglycan and collagen synthesis in human OA cartilage. In addition to its well-established effect on subchondral bone, calcitonin may prove beneficial to the management of joint diseases through direct effects on chondrocytes.
Highlights
Calcitonin has been demonstrated to have chondroprotective effects under pre-clinical settings
Current drug development strategies have focused on inhibition of the enzymes responsible for degradation of these extra-cellular matrix (ECM) molecules, mainly the matrix metalloproteinases (MMPs) and the aggrecanases a disintegrin and metalloproteinase with thrombospondin motifs (ADAM-TS), which have resulted in potent Matrix metalloproteinases (MMP) and aggrecanase inhibitors [6]
Calcitonin stimulates proteoglycan synthesis in human articular cartilage explants The effects of salmon calcitonin on human articular cartilage proteoglycan synthesis were investigated in response to different doses (100 pM-100 nM)
Summary
Calcitonin has been demonstrated to have chondroprotective effects under pre-clinical settings. It is debated whether this effect is mediated through subchondral-bone, directly on cartilage or both in combination. We investigated possible direct effects of salmon calcitonin on proteoglycans and collagen-type-II synthesis in osteoarthritic (OA) cartilage. Key characteristic of the disease are the accelerated degeneration of articular cartilage, changes in the matrix structure, and sclerosis of the subchondral bone. OA is a complicated condition of the entire joint, involving cartilage, bone, and the synovium, which highlights the complexity of the disease and may provide some understanding of why current treatments have not been successful [2,3,4]. Besides preclinical efficacy, these treatment opportunities have yet to demonstrate clinical efficacy and have been implicated in the development of adverse musculoskeletal events [2]
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