Evidence for direct actions of melanocortin peptides on bone metabolism

Dumont, Laurence M.; Wu, Chia-Shan; Tatnell, Michele A.; Cornish, Jillian; Mountjoy, Kathleen G.

doi:10.1016/j.peptides.2004.12.034

Cited by 25 publications

(18 citation statements)

References 27 publications

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“…We cannot exclude compensatory effects of other MCR subtypes in bone tissue, i.e. MC2 and MC4, for which at least mRNA transcripts are found in osteoblasts [17], [27]. In addition to matrix producing osteoblasts, bone contains also matrix degrading cells, the osteoclasts which express MC2, MC3, MC4 and MC5 transcripts [17].…”

Section: Discussionmentioning

confidence: 96%

Melanocortin 1 Receptor-Signaling Deficiency Results in an Articular Cartilage Phenotype and Accelerates Pathogenesis of Surgically Induced Murine Osteoarthritis

et al. 2014

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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.

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Section: Discussionmentioning

confidence: 96%

Melanocortin 1 Receptor-Signaling Deficiency Results in an Articular Cartilage Phenotype and Accelerates Pathogenesis of Surgically Induced Murine Osteoarthritis

et al. 2014

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“…Additionally, there is some evidence to suggest that melanocortin signaling has direct influences on bone. The MC4R is expressed both on osteoblasts and osteoclasts [21], [22], demonstrating the potential for melanocortin peptides to directly influence bone metabolism. While increased bone mass has been previously described in the MC4RKO mouse, our study is the first to show that bone strength is also increased by MC4R deficiency.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Lean Mass, Bone Mass, and Exercise Tolerance by the Central Melanocortin System

et al. 2012

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Signaling via the type 4-melanocortin receptor (MC4R) is an important determinant of body weight in mice and humans, where loss of function mutations lead to significant obesity. Humans with mutations in the MC4R experience an increase in lean mass. However, the simultaneous accrual of fat mass in such individuals may contribute to this effect via mechanical loading. We therefore examined the relationship of fat mass and lean mass in mice lacking the type-4 melanocortin receptor (MC4RKO). We demonstrate that MC4RKO mice display increased lean body mass. Further, this is not dependent on changes in adipose mass, as MC4RKO mice possess more lean body mass than diet-induced obese (DIO) wild type mice with equivalent fat mass. To examine potential sources of the increased lean mass in MC4RKO mice, bone mass and strength were examined in MC4RKO mice. Both parameters increase with age in MC4RKO mice, which likely contributes to increases in lean body mass. We functionally characterized the increased lean mass in MC4RKO mice by examining their capacity for treadmill running. MC4R deficiency results in a decrease in exercise performance. No changes in the ratio of oxidative to glycolytic fibers were seen, however MC4RKO mice demonstrate a significantly reduced heart rate, which may underlie their impaired exercise performance. The reduced exercise capacity we report in the MC4RKO mouse has potential clinical ramifications, as efforts to control body weight in humans with melanocortin deficiency may be ineffective due to poor tolerance for physical activity.

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“…MC2R and MC5R are receptors for adrenocorticotropic hormone (ACTH) and melanocyte-stimulating hormones (MSH). A similar gene, melanocortin-4 receptor ( MC4R ), has been shown to be expressed in periosteum and in osteoblasts in the mouse and it is possible that MC2R and MC5R are likewise involved in the regulation of bone formation [Dumont et al, 2005]. RBBP8 is found among several proteins that bind directly to the retinoblastoma protein, which regulates cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Isolated skeletal malformations in a child with a small mosaic ring microduplication of 18 p11.21q11.2: Genotype–phenotype correlations

Slavin

Kuruvilla

Curtis

et al. 2011

American J of Med Genetics Pt A

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We describe a developmentally normal Amish child who has a karyotype with 47 chromosomes, including a supernumerary ring-shaped chromosome 18 in each metaphase studied. The only phenotypic findings in the patient were hemivertebrae and rib anomalies. Further analysis of interphase cells revealed an additional, less frequent mosaic, apparently normal cell population. Genes in the triplicated region that possibly are contributing to her skeletal phenotype include GATA6, MC2R, MC5R, RBBP8, ESCO1, and ROCK1, among others. By studying such patients with abnormal genetic dosage, genotype–phenotype correlations can be used to refine gene function.

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Evidence for direct actions of melanocortin peptides on bone metabolism

Cited by 25 publications

References 27 publications

Melanocortin 1 Receptor-Signaling Deficiency Results in an Articular Cartilage Phenotype and Accelerates Pathogenesis of Surgically Induced Murine Osteoarthritis

Melanocortin 1 Receptor-Signaling Deficiency Results in an Articular Cartilage Phenotype and Accelerates Pathogenesis of Surgically Induced Murine Osteoarthritis

Regulation of Lean Mass, Bone Mass, and Exercise Tolerance by the Central Melanocortin System

Isolated skeletal malformations in a child with a small mosaic ring microduplication of 18 p11.21q11.2: Genotype–phenotype correlations

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