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

Abstract

Adrenomedullin (ADM), a member of the calcitonin family of peptides, is a potent vasodilator and was shown to have the ability to modulate bone metabolism. We have previously found a unique cell surface antigen (Kat1 antigen) expressed in rat osteoclasts, which is involved in the functional regulation of the calcitonin receptor (CTR). Cross-linking of cell surface Kat1 antigen with anti-Kat1 antigen monoclonal antibody (mAbKat1) stimulated osteoclast formation only under conditions suppressed by calcitonin. Here, we found that ADM provoked a significant stimulation in osteoclastogenesis only in the presence of calcitonin; a similar biological effect was seen with mAbKat1 in the bone marrow culture system. This stimulatory effect on osteoclastogenesis mediated by ADM was abolished by the addition of mAbKat1. 125I-labeled rat ADM (125I-ADM)-binding experiments involving micro-autoradiographic studies demonstrated that mononuclear precursors of osteoclasts abundantly expressed ADM receptors, and the specific binding of 125I-ADM was markedly inhibited by the addition of mAbKat1, suggesting a close relationship between the Kat1 antigen and the functional ADM receptors expressed on cells in the osteoclast lineage. ADM receptors were also detected in the osteoclast progenitor cells in the late mitotic phase, in which only one daughter cell of the dividing cell express ADM receptors, suggesting the semiconservative cell division of the osteoclast progenitors in the initiation of osteoclastogenesis. Messenger RNAs for the receptor activity-modifying-protein 1 (RAMP1) and calcitonin receptor-like receptor (CRLR) were expressed in cells in the osteoclast lineage; however, the expression of RAMP2 or RAMP3 was not detected in these cells. It is suggested that the Kat1 antigen is involved in the functional ADM receptor distinct from the general ADM receptor, consisting of CRLR and RAMP2 or RAMP3. Modulation of osteoclastogenesis through functional ADM receptors abundantly expressed on mononuclear osteoclast precursors is supposed to be important in the fine regulation of osteoclast differentiation in a specific osteotrophic hormonal condition with a high level of calcitonin in blood.

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Fig. 1: Histological relationship between osteoclasts and blood vessels.
Fig. 2: Stimulation of osteoclastic MNC formation by ADM only when cells are treated with calcitonin.
Fig. 3: Osteoclast-specific mAbKat1 blocked ADM-induced osteoclastogenesis in the presence of calcitonin.
Fig. 4: Detection of specific receptors for ADM on cells in culture of osteoclastogenesis and inhibition of 125I-ADM binding to cells in the osteoclast lineage by mAbKat1.
Fig. 5: Detection of specific receptors for ADM on osteoclastic cell lineage analyzed by autoradiography and RT-PCR.
Fig. 6: Schematic demonstration of the expression of functional ADM receptors related to osteoclast-specific Kat1 antigen in cells in the osteoclast lineage.

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TK and AK performed the study concept and design. TK, HH, TY, IT, and AK performed the development of methodology and writing, review, and revision of the paper. TK, HH, and AK provided acquisition of data and statistical analysis. JG, JZ, YK-N, NU, SM, and SS provided technical and material support. All authors read and approved the final paper.

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Correspondence to Toshio Kukita.

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This work was supported in part by a Grant for Scientific Research from the Japanese Ministry of Education, Science and Culture (Project 09671858, 15K15677, and 18K09506).

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The authors declare no competing interests.

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Kukita, T., Hiura, H., Gu, JY. et al. Modulation of osteoclastogenesis through adrenomedullin receptors on osteoclast precursors: initiation of differentiation by asymmetric cell division. Lab Invest 101, 1449–1457 (2021). https://doi.org/10.1038/s41374-021-00633-2

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