Bone phenotype in melanocortin 2 receptor-deficient mice

Abstract

Considering that stress condition associated with osteoporosis, the hypothalamic-pituitary-adrenal (HPA) axis, which is essential for central stress response system, is implicated in regulating bone mass accrual. Melanocortin 2 receptor (MC2R), the receptor of adrenocorticotropic hormone is expressed in both adrenal gland cells and bone cells. To elucidate the role of HPA axis in bone metabolism, we assessed the skeletal phenotype of MC2R deficient mice ( MC2R −/− mice). We first examined bone mineral density and cortical thickness of femur using dual x-ray absorptiometry and micro-computed tomography. We then conducted histomorphometric analysis to calculate the static and dynamic parameters of vertebrae in MC2R −/− mice. The levels of osteoblastic marker genes were examined by quantitative PCR in primary osteoblasts derived from MC2R −/− mice. Based on these observations, bone mineral density of femur in MC2R −/− mice was increasing relative to litter controls. Meanwhile, the thickness of cortical bone of femur in MC2R −/− mice was remarkably elevated. Moreover, serum osteocalcin level was drastically raised in MC2R −/− mice. However, bone histomorphometry revealed that static and dynamic parameters reflecting bone formation and resorption were unchanged in vertebrae of MC2R −/− mice compared to the control, indicating that MC2R function may be specific to appendicular bone than axis bone. Taken together, the HPA axis due to deletion of MC2R is involved in bone metabolism.

Transferrin receptor 1-mediated iron uptake regulates bone mass in mice via osteoclast mitochondria and cytoskeleton

“…Our qPCR result demonstrated that deletion efficiency of Tfr1 gene, Tfrc , in vertebra is less than femurs ( Figure 2—figure supplement 9 ). It is also likely that the different physical properties, remodeling rate, microenvironment, and the heterogeneous osteoclast subtypes in the distinct sites and compartments of bone may contribute to these site- and compartment-specific phenotypes which have been reported in other genetically modified mouse models ( Cruz Grecco Teixeira et al, 2016 and Sato et al, 2020 ).…”

A rare homozygous variant of MC2R gene identified in a Chinese family with familial glucocorticoid deficiency type 1: A case report

“…Various melanocortin receptors are expressed in bone cells, and activation of melanocortin receptors can cause increased proliferation and expression of a variety of genes in osteoblastic cells (19). In MC2R -/-mice, bone mineral density as well as the thickness of the cortical bone of femur increased (20). Because the FGD1 patients had excess ACTH even after cortisol treatment, activation of other melanocortin receptors in bone cells may account for their tall stature.…”

A Novel Mutation in Melanocortin Receptor 2 and a Reported Mutation in Melanocortin Receptor 2 Accessory Protein: Three Chinese Cases with Familial Glucocorticoid Deficiency

“…This observation may, to some extent, suggest that MC2R does not affect height through the activation of growth hormone/insulin-like growth factor-1 axis. A mouse model of MC2R-deficient (MC2R −/− ) mice displayed abnormal bone metabolism, but no growth abnormality was observed [Sato et al, 2020]. B6N5 generations of MC2R −/− mice showed normal development and function of reproductive organs but did not grow abnormally [Chida et al, 2009].…”