Abstract
Proopiomelanocortin-derived peptides exert pleiotropic effects via binding to melanocortin receptors (MCR). MCR-subtypes have been detected in cartilage and bone and mediate an increasing number of effects in diathrodial joints. This study aims to determine the role of MC1-receptors (MC1) in joint physiology and pathogenesis of osteoarthritis (OA) using MC1-signaling deficient mice (Mc1re/e). OA was surgically induced in Mc1re/e and wild-type (WT) mice by transection of the medial meniscotibial ligament. Histomorphometry of Safranin O stained articular cartilage was performed with non-operated controls (11 weeks and 6 months) and 4/8 weeks past surgery. µCT–analysis for assessing epiphyseal bone architecture was performed as a longitudinal study at 4/8 weeks after OA-induction. Collagen II, ICAM-1 and MC1 expression was analysed by immunohistochemistry. Mc1re/e mice display less Safranin O and collagen II stained articular cartilage area compared to WT prior to OA-induction without signs of spontaneous cartilage surface erosion. This MC1-signaling deficiency related cartilage phenotype persisted in 6 month animals. At 4/8 weeks after OA-induction cartilage erosions were increased in Mc1re/e knees paralleled by weaker collagen II staining. Prior to OA-induction, Mc1re/e mice do not differ from WT with respect to bone parameters. During OA, Mc1re/e mice developed more osteophytes and had higher epiphyseal bone density and mass. Trabecular thickness was increased while concomitantly trabecular separation was decreased in Mc1re/e mice. Numbers of ICAM-positive chondrocytes were equal in non-operated 11 weeks Mc1re/e and WT whereas number of positive chondrocytes decreased during OA-progression. Unchallenged Mc1re/e mice display smaller articular cartilage covered area without OA-related surface erosions indicating that MC1-signaling is critical for proper cartilage matrix integrity and formation. When challenged with OA, Mc1re/e mice develop a more severe OA-pathology. Our data suggest that MC1-signaling protects against cartilage degradation and subchondral bone sclerosis in OA indicating a beneficial role of the POMC system in joint pathophysiology.
Highlights
Osteoarthritis is an age-related and/or trauma-induced multifactorial, slowly progressing degenerative disorder of the synovial joints culminating in the irreversible destruction of the articular cartilage
Inflammatory-like processes originated from OA increase bone and cartilage turnover and eventually lead to degradation of these tissues
Inactivation of the MC1, which is present on chondrocytes and cells of epiphyseal bone will have an effect on physiology and pathophysiology of diathrodial joint tissues
Summary
Osteoarthritis is an age-related and/or trauma-induced multifactorial, slowly progressing degenerative disorder of the synovial joints culminating in the irreversible destruction of the articular cartilage. Besides chondrocytes and cartilage as mediators of OA other cells and tissues of the joint like synovium or subchondral bone modulate OA-pathogenesis. Subchondral bone and articular cartilage are separated through the tide mark region and have a close relationship during progression of OA. Abnormal calcification of this tide mark region during OA leads to a decrease in cartilage thickness and increased subchondral plate thickness [5] preceded by increased turnover of subchondral bone, thinning trabecular structures, sclerosis of the subchondral plate, bone marrow lesions and subchondral bone cysts [6,7]. Alterations in subchondral bone remodeling add to biomechanical changes and enhance OA progression [8,9]
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