Modulation of osteoclastogenesis through adrenomedullin receptors on osteoclast precursors: initiation of differentiation by asymmetric cell division

Kukita, Toshio; Hiura, Hidenobu; Gu, Jian; Zhang, Jing Qi; Kyumoto‐Nakamura, Yukari; Uehara, Norihisa; Murata, Sara; Sonoda, Soichiro; Yamaza, Takayoshi; Takahashi, Ichiro; Kukita, Akiko

doi:10.1038/s41374-021-00633-2

Cited by 2 publications

(1 citation statement)

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“…Calcrl and its co-receptors, namely receptor activity modifying protein (RAMP) 1, RAMP2, or RAMP3, bind calcitonin gene-related peptide (CGRP) or adrenomedullin (ADM) [ 37 ]. Calcrl is expressed in the membranes of osteoclast precursors, but the ADM- and CGRP-dependent function of Calcrl during osteoclastogenesis remains ambiguous [ 38 ]. Here, we clarified a novel function of Calcrl as a key factor for osteoclast fusion, as our findings suggested that cell fusion was blocked in Calcrl -deficient RAW 264.7 cells.…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Genes for Cell Fusion during Osteoclast Formation

Cho

Cheon²,

Ding³

et al. 2022

IJMS

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Osteoclasts are derived from hematopoietic stem cells. Monocyte preosteoclasts obtain resorbing activity via cell–cell fusion to generate multinucleated cells. However, the mechanisms and molecules involved in the fusion process are poorly understood. In this study, we performed RNA sequencing with single nucleated cells (SNCs) and multinucleated cells (MNCs) to identify the fusion-specific genes. The SNCs and MNCs were isolated under the same conditions during osteoclastogenesis with the receptor activator of nuclear factor-κB ligand (RANKL) administration. Based on this analysis, the expression of seven genes was found to be significantly increased in MNCs but decreased in SNCs, compared to that in bone marrow-derived macrophages (BMMs). We then generated knockout macrophage cell lines using a CRISPR-Cas9 genome-editing tool to examine their function during osteoclastogenesis. Calcrl-, Marco-, or Ube3a-deficient cells could not develop multinucleated giant osteoclasts upon RANKL stimulation. However, Tmem26-deficient cells fused more efficiently than control cells. Our findings demonstrate that Calcrl, Marco, and Ube3a are novel determinants of osteoclastogenesis, especially with respect to cell fusion, and highlight potential targets for osteoporosis therapy.

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Section: Discussionmentioning

confidence: 99%