Bone phenotype in melanocortin 2 receptor-deficient mice

Tsuyoshi Sato; Takanori Iwata; Michihiko Usui; Shoichiro Kokabu; Yasutaka Sugamori; Yuki Takaku; Takashi Kobayashi; Ko Ito; Masahito Matsumoto; Shu Takeda; Ren Xu; Dai Chida

doi:10.1016/j.bonr.2020.100713

Bone phenotype in melanocortin 2 receptor-deficient mice

Bone Rep. 2020 Aug 30:13:100713. doi: 10.1016/j.bonr.2020.100713. eCollection 2020 Dec.

Authors

Tsuyoshi Sato¹, Takanori Iwata², Michihiko Usui³, Shoichiro Kokabu⁴, Yasutaka Sugamori¹, Yuki Takaku¹, Takashi Kobayashi¹, Ko Ito¹, Masahito Matsumoto⁵, Shu Takeda⁶, Ren Xu⁷, Dai Chida^{1

8}

Affiliations

¹ Department of Oral and Maxillofacial Surgery, Saitama Medical University, Saitama, Japan.
² Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
³ Division of Periodontology, Department of Cardiology and Periodontology, Kyushu Dental University, Fukuoka, Japan.
⁴ Division of Molecular Signaling and Biochemistry, Department of Health Promotion, Kyushu Dental University, Kokurakita-ku, Kitakyushu, Fukuoka, Japan.
⁵ Department of Biofunction Research, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan.
⁶ Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan.
⁷ State Key Laboratory of Cellular Stress Biology, School of Medicine, Xiamen University, Xiamen, China.
⁸ SanBio, Tokyo, Japan.

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.

Keywords: ACTH, adrenocorticotropic hormone; Bone metabolism; FGD, familial glucocorticoid deficiency; GCs, Glucocorticoids; HPA axis, hypothalamic-pituitary-adrenal axis; HSD, hydroxysteroid dehydrogenase; Hypothalamic-pituitary-adrenal axis; MC2R, melanocortin 2 receptor; Melanocortin 2 receptor; Osteocalcin.