Melanocortin 1 receptor-signaling deficiency results in an articular cartilage phenotype and accelerates pathogenesis of surgically induced murine osteoarthritis

PLoS One. 2014 Sep 5;9(9):e105858. doi: 10.1371/journal.pone.0105858. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental
  • Bone Density
  • Cartilage, Articular / metabolism*
  • Cartilage, Articular / pathology*
  • Collagen Type II / metabolism
  • Disease Models, Animal
  • Intercellular Adhesion Molecule-1 / metabolism
  • Knee Joint / metabolism
  • Knee Joint / pathology
  • Male
  • Matrix Metalloproteinase 13 / metabolism
  • Menisci, Tibial / pathology
  • Mice
  • Osteoarthritis / diagnosis
  • Osteoarthritis / etiology*
  • Osteoarthritis / pathology*
  • Osteophyte / metabolism
  • Phenotype*
  • Postoperative Complications*
  • Receptor, Melanocortin, Type 1 / metabolism*
  • Signal Transduction*
  • Time Factors

Substances

  • Collagen Type II
  • Receptor, Melanocortin, Type 1
  • Intercellular Adhesion Molecule-1
  • Matrix Metalloproteinase 13

Grants and funding

This work was funded by the DFG, and the grant No. GR1301/9-1 was assigned to SG and MB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.