title: Melanocortin 1 receptor-signaling deficiency results in an articular cartilage phenotype and accelerates pathogenesis of surgically induced murine osteoarthritis.
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.
authors.affiliation: Experimental Orthopedics, University Hospital of Regensburg, Regensburg, Bavaria, Germany; Orthopedic Surgery, University Hospital of Regensburg, Bad Abbach, Bavaria, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Lorenz
authors.affiliation: Research Centre for Experimental Orthopedics, Orthopedic University Hospital Heidelberg, Heidelberg, Baden-Württemberg, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Seebach
authors.affiliation: Experimental Orthopedics, University Hospital of Regensburg, Regensburg, Bavaria, Germany; Dermatology, University Hospital of Münster, Münster, North Rhine-Westphalia, Germany.
authors.forename: Gerit
authors.initials: G
authors.lastname: Hackmayer
authors.affiliation: Research Centre for Experimental Orthopedics, Orthopedic University Hospital Heidelberg, Heidelberg, Baden-Württemberg, Germany.
authors.forename: Carina
authors.initials: C
authors.lastname: Greth
authors.affiliation: Oral and Maxillofacial Surgery, University Hospital of Regensburg, Regensburg, Bavaria, Germany.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bauer
authors.affiliation: TIP Immunology, Merck Serono Global Research & Development, Darmstadt, Hessen, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kleinschmidt
authors.affiliation: Medical Hospital B, University Hospital of Münster, Münster, North Rhine-Westphalia, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Bettenworth
authors.affiliation: Dermatology, University Hospital of Münster, Münster, North Rhine-Westphalia, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Böhm
authors.affiliation: Orthopedic Surgery, University Hospital of Regensburg, Bad Abbach, Bavaria, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Grifka
authors.affiliation: Experimental Orthopedics, University Hospital of Regensburg, Regensburg, Bavaria, Germany; Orthopedic Surgery, University Hospital of Regensburg, Bad Abbach, Bavaria, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Grässel
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental; D015519:Bone Density; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology*; D024043:Collagen Type II / Q000378:metabolism; D004195:Disease Models, Animal; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007719:Knee Joint / Q000378:metabolism / Q000473:pathology; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D008592:Menisci, Tibial / Q000473:pathology; D051379:Mice; D010003:Osteoarthritis / Q000175:diagnosis / Q000209:etiology* / Q000473:pathology*; D054850:Osteophyte / Q000378:metabolism; D010641:Phenotype; D011183:Postoperative Complications; D044102:Receptor, Melanocortin, Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D024043:Collagen Type II; D044102:Receptor, Melanocortin, Type 1; D018799:Intercellular Adhesion Molecule-1; D053509:Matrix Metalloproteinase 13