Modulation of osteoclastogenesis through adrenomedullin receptors on osteoclast precursors: initiation of differentiation by asymmetric cell division
Modulation of osteoclastogenesis through adrenomedullin receptors on osteoclast precursors: initiation of differentiation by asymmetric cell division
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DOI：
10.1038/s41374-021-00633-2
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发表时间：
2021-10-05
影响因子：
5
通讯作者：
Kukita，Akiko
中科院分区：
文献类型：
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作者：
Kukita，Toshio;Hiura，Hidenobu;Kukita，Akiko
肾上腺髓质素(adrenomedullin，ADM)是降钙素家族多肽的一员，是一种强有力的血管扩张剂，具有调节骨代谢的能力。我们以前发现了一种独特的细胞表面抗原(Kat1抗原)，它在大鼠破骨细胞中表达，参与降钙素受体(CTR)的功能调节。只有在降钙素抑制的条件下，细胞表面Kat1抗原与抗Kat1抗原单抗(MAbKat1)的交联才能刺激破骨细胞的形成。在这里，我们发现，只有在降钙素存在的情况下，ADM才能在破骨细胞生成中产生显著的刺激作用；在骨髓培养系统中，mAbKat1也有类似的生物学效应。加入mAbKat1.125I标记的大鼠ADM(125I-ADM)结合显微放射自显影实验证明，破骨细胞的单核前体细胞大量表达ADM受体，mAbKat1可显著抑制125I-ADM的特异性结合，提示Kat1抗原与破骨细胞系细胞上表达的功能性ADM受体密切相关。在有丝分裂晚期，破骨细胞和前体细胞中也检测到ADM受体，分裂细胞中只有一个子细胞表达ADM受体，提示破骨细胞前体细胞在启动破骨细胞生成过程中处于半保存性细胞分裂状态。破骨细胞系中的细胞表达受体活性修饰蛋白1(RAMP1)和降钙素受体样受体(CRLR)的信使RNA，而RAMP2和RAMP3在这些细胞中不表达。提示Kat1抗原参与了功能性的ADM受体，不同于一般的ADM受体，它由CRLR和RAMP2或RAMP3组成。单核破骨细胞前体细胞上大量表达的功能性ADM受体对破骨细胞的形成具有重要的调控作用，在血液中存在高水平降钙素的特定促骨激素条件下，对破骨细胞分化的精细调控具有重要意义。
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 of125I-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.