Accelerated Development With Increased Bone Mass and Skeletal Response to Loading Suggest Receptor Activity Modifying Protein-3 as a Bone Anabolic Target.
Accelerated Development With Increased Bone Mass and Skeletal Response to Loading Suggest Receptor Activity Modifying Protein-3 as a Bone Anabolic Target.
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DOI：
10.3389/fendo.2021.807882
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发表时间：
2021
影响因子：
5.2
通讯作者：
Skerry TM
中科院分区：
文献类型：
--
作者：
Pacharne S;Livesey M;Kadmiel M;Wang N;Caron KM;Richards GO;Skerry TM
基因敲除技术提供了对基因的生理作用的洞察。启动的异构体G蛋白偶联受体内分泌学研究包括缺失受体活性修改蛋白-3，这是一种改变降钙素和降钙素样受体的配基选择性的辅助蛋白。最初，Ramp3-/-的缺失似乎表现为沉默，但后来发现，小鼠具有高骨量表型，血管生成、胰淀素稳态以及肾上腺髓质素对心血管和淋巴系统的影响比例较小。在这里，我们详细地探讨了Ramp3/-缺失对骨骼生长发育、骨量和模拟运动的机械负荷的骨反应的影响。缺乏RAMP3的小鼠是健康和有活力的，通过特定骨骼的矿化程度和MicroCT测量来评估骨骼的加速发育。具体地说，我们观察到，新生儿和幼鼠后肢和脊椎的骨量和矿化增加，骨小梁厚度增加。这些变化与Ramp3-/-小鼠的成骨细胞数量和骨沉积率增加以及骨痂生长板细胞增殖增加有关。影响在出生后几周内持续，但RAMP3和WT小鼠之间的总骨量差异在老年动物中失去了显著意义，尽管结构差异仍然存在。在RAMP3-/-小鼠中，17周龄小鼠的骨骼对机械负荷的反应与剧烈运动的效果相似，比WT对照组小鼠显著增加30%。对RAMP3-/-小鼠培养的成骨细胞的研究表明，RAMPs1和RAMP2和RAMP2和RAMP3之间存在相互作用。我们的初步数据显示，RAMP3-/-成骨细胞增加了β-连环蛋白的表达，这是已知调节骨骼动态平衡和机械敏感性的典型WNT信号通路的一个组成部分。鉴于RAMP与降钙素和降钙素样受体相互作用改变配体选择性，以及与其他GPCRs改变运输或配体偏向，目前尚不清楚Ramp3/-小鼠的骨表型是由于一个或多个GPCRs介导的信号改变所致。然而，随着RAMP相互作用受体的拮抗剂越来越多，操纵RAMP3信号系统似乎有可能在治疗上提供合成代谢效应。
Knockout technologies provide insights into physiological roles of genes. Studies initiated into endocrinology of heteromeric G protein-coupled receptors included deletion of receptor activity modifying protein-3, an accessory protein that alters ligand selectivity of calcitonin and calcitonin-like receptors. Initially, deletion of Ramp3-/- appeared phenotypically silent, but it has emerged that mice have a high bone mass phenotype, and more subtle alterations to angiogenesis, amylin homeostasis, and a small proportion of the effects of adrenomedullin on cardiovascular and lymphatic systems. Here we explore in detail, effects of Ramp3-/- deletion on skeletal growth/development, bone mass and response of bone to mechanical loading mimicking exercise. Mouse pups lacking RAMP3 are healthy and viable, having accelerated development of the skeleton as assessed by degree of mineralisation of specific bones, and by microCT measurements. Specifically, we observed that neonates and young mice have increased bone volume and mineralisation in hindlimbs and vertebrae and increased thickness of bone trabeculae. These changes are associated with increased osteoblast numbers and bone apposition rate in Ramp3-/- mice, and increased cell proliferation in epiphyseal growth plates. Effects persist for some weeks after birth, but differences in gross bone mass between RAMP3 and WT mice lose significance in older animals although architectural differences persist. Responses of bones of 17-week old mice to mechanical loading that mimics effects of vigorous exercise is increased significantly in Ramp3-/- mice by 30% compared with WT control mice. Studies on cultured osteoblasts from Ramp3-/- mice indicate interactions between mRNA expression of RAMPs1 and 3, but not RAMP2 and 3. Our preliminary data shows that Ramp3-/- osteoblasts had increased expression β-catenin, a component of the canonical Wnt signalling pathway known to regulate skeletal homeostasis and mechanosensitivity. Given interactions of RAMPs with both calcitonin and calcitonin-like receptors to alter ligand selectivity, and with other GPCRs to change trafficking or ligand bias, it is not clear whether the bone phenotype of Ramp3-/- mice is due to alterations in signalling mediated by one or more GPCRS. However, as antagonists of RAMP-interacting receptors are growing in availability, there appears the likelihood that manipulation of the RAMP3 signalling system could provide anabolic effects therapeutically.
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影响因子：
--
作者：
Cornish, J;Naot, D;Reid, IR
通讯作者：
Reid, IR
影响因子：
64.8
作者：
Gao X;Zhang D;Xu C;Li H;Caron KM;Frenette PS
通讯作者：
Frenette PS
影响因子：
--
作者：
Cardiff, Robert D;Miller, Claramae H;Munn, Robert J
通讯作者：
Munn, Robert J
影响因子：
13.3
作者：
Buckley, Lenore;Guyatt, Gordon;McAlindon, Timothy
通讯作者：
McAlindon, Timothy
影响因子：
4
作者：
Granholm, Susanne;Lundberg, Pernilla;Lerner, Ulf H.
通讯作者：
Lerner, Ulf H.