Sustained RANKL Response to Parathyroid Hormone in Oncostatin M Receptor-Deficient Osteoblasts Converts Anabolic Treatment to a Catabolic Effect In Vivo
Sustained RANKL Response to Parathyroid Hormone in Oncostatin M Receptor-Deficient Osteoblasts Converts Anabolic Treatment to a Catabolic Effect In Vivo
复制标题
甲状旁腺素 M 受体缺陷的成骨细胞对甲状旁腺素的持续 RANKL 反应将体内同化治疗转化为分解代谢效应
DOI：
10.1002/jbmr.1506
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发表时间：
2012-04-01
影响因子：
6.2
通讯作者：
Sims, Natalie A.
中科院分区：
文献类型：
--
作者：
Walker, Emma C.;Poulton, Ingrid J.;Sims, Natalie A.
甲状旁腺激素（PTH）是唯一批准用于骨质疏松症治疗的合成代谢药物。它通过成骨细胞刺激破骨细胞形成和骨形成，这两种活性之间的平衡由给药方式决定。抑瘤素M（OSM）是一种由成骨细胞系细胞表达的gp 130依赖性细胞因子，在成骨细胞系中具有相似的作用和相似的基因靶点。在这项研究中，我们调查OSM是否可能参与PTH的合成代谢作用。PTH处理的鼠基质细胞和原代颅骨成骨细胞的微阵列分析和定量实时聚合酶链反应（qPCR）鉴定了gp 130和gp 130依赖性辅助受体和配体的显著调节，包括OSM受体（OSMR）表达的显著增加。为了确定OSMR信号传导是否是PTH合成代谢作用所必需的，用hPTH（134）处理6周龄雄性Osmr-/-小鼠和野生型（WT）同窝出生的小鼠3周。在WT小鼠中，PTH增加骨小梁体积和骨小梁厚度。相比之下，相同的治疗在Osmr-/-小鼠中具有分解代谢作用，减少了骨小梁体积和骨小梁数量。与WT小鼠相比，Osmr-/-小鼠对PTH的反应中成骨细胞形成和矿物质沉积率增加的任何变化都不能解释这一点。相反，PTH治疗使Osmr-/-小鼠中的破骨细胞表面加倍，在WT小鼠中未观察到这种作用。与这一发现相一致，当破骨细胞前体细胞在成骨细胞的存在下培养时，当使用Osmr-/-成骨细胞时，更多的破骨细胞响应于PTH而形成。在Osmr-/-成骨细胞中，PTH 1 R mRNA水平和cAMP对PTH的反应均未改变。然而，PTH处理的Osmr-/-成骨细胞中的RANKL诱导至少持续到24？在PTH暴露后24小时，在WT成骨细胞中未观察到效果。这些数据表明，间歇性PTH给药引起的短暂RANKL诱导（与其合成代谢作用相关）在OSMR缺陷型成骨细胞中变为长期诱导，导致骨破坏。(c)2012年美国骨与矿物质研究学会。
Parathyroid hormone (PTH) is the only approved anabolic agent for osteoporosis treatment. It acts via osteoblasts to stimulate both osteoclast formation and bone formation, with the balance between these two activities determined by the mode of administration. Oncostatin M (OSM), a gp130-dependent cytokine expressed by osteoblast lineage cells, has similar effects and similar gene targets in the osteoblast lineage. In this study, we investigated whether OSM might participate in anabolic effects of PTH. Microarray analysis and quantitative real-time polymerase chain reaction (qPCR) of PTH-treated murine stromal cells and primary calvarial osteoblasts identified significant regulation of gp130 and gp130-dependent coreceptors and ligands, including a significant increase in OSM receptor (OSMR) expression. To determine whether OSMR signaling is required for PTH anabolic action, 6-week-old male Osmr-/- mice and wild-type (WT) littermates were treated with hPTH(134) for 3 weeks. In WT mice, PTH increased trabecular bone volume and trabecular thickness. In contrast, the same treatment had a catabolic effect in Osmr-/- mice, reducing both trabecular bone volume and trabecular number. This was not explained by any alteration in the increased osteoblast formation and mineral apposition rate in response to PTH in Osmr-/- compared with WT mice. Rather, PTH treatment doubled osteoclast surface in Osmr-/- mice, an effect not observed in WT mice. Consistent with this finding, when osteoclast precursors were cultured in the presence of osteoblasts, more osteoclasts were formed in response to PTH when Osmr-/- osteoblasts were used. Neither PTH1R mRNA levels nor cAMP response to PTH were modified in Osmr-/- osteoblasts. However, RANKL induction in PTH-treated Osmr-/- osteoblasts was sustained at least until 24?hours after PTH exposure, an effect not observed in WT osteoblasts. These data indicate that the transient RANKL induction by intermittent PTH administration, which is associated with its anabolic action, is changed to a prolonged induction in OSMR-deficient osteoblasts, resulting in bone destruction. (c) 2012 American Society for Bone and Mineral Research.