Modulation of insulin-like growth factor 1 levels in human osteoarthritic subchondral bone osteoblasts
Modulation of insulin-like growth factor 1 levels in human osteoarthritic subchondral bone osteoblasts
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DOI：
10.1016/j.bone.2005.09.007
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发表时间：
2006-03-01
期刊：
影响因子：
4.1
通讯作者：
Lajeunesse, D
中科院分区：
文献类型：
--
作者：
Massicotte, F;Fernandes, JC;Lajeunesse, D
人类骨关节炎（OA）的特征是软骨损失、骨质硬化、骨赘形成和滑膜炎症。我们之前报道过 OA 成骨细胞 (Ob) 显示出可能导致骨硬化的异常表型特征，并且可以通过 OA Ob 内源性前列腺素 E-2 (PGE(2)) 的低或高内源性产生来识别 OA 患者的两个亚组。在这里，我们确定，与正常和低 OA Ob 相比，高 OA 亚组中 PGE2 水平升高与环氧合酶 2 (COX-2) 蛋白水平升高有关。 OA Ob 中内源性 PGE2 水平与胰岛素样生长因子 I (IGF-1) 水平之间观察到线性关系。由于甲状旁腺激素 (PTH) 和 PGE(2) 是 Ob 中已知的 IGF-1 产生刺激剂，因此我们接下来评估了它们在 OA Ob 中的作用。两个亚组对 PGE2 的反应均类似地增加了 IGF-1 的产生，而与低 OA 组相比，高 OA 亚组对 PTH 的反应较弱。相反，当使用萘普生（一种抑制环氧合酶（COX）的非甾体抗炎药（NSAID））减少 PGE2 合成时，只有高 OA 组显示出对 IGF-1 产生的显着抑制。 PGE(2) 依赖性 IGF-1 合成刺激部分归因于 cAMP/蛋白激酶 A 途径，因为用 H-89 直接抑制该途径以及抑制与 cAMP 产生相关的 EP2 或 EP4 受体，都会减少 IGF-1 合成。与正常 Ob 相比，OA 组骨组织中最丰富的 IGF-1 结合蛋白 (IGFBP) IGFBP-3、-4 和 -5 的产生量较低，与 OA 组无关。基础条件下，OA Ob表达与正常Ob相似的IGF-1 mRNA；然而，PGE2 在 OA 中比正常 Ob 更能刺激 IGF-1 mRNA 表达。这些数据表明，OA Ob 中 IGF-1 水平升高与内源性 PGE2 水平升高相关，并且 OA Ob 中较高的 IGF-1 水平可能对 OA 骨硬化很重要。 (c) 2005 Elsevier Inc. 保留所有权利。
Human osteoarthritis (OA) is characterized by cartilage loss, bone sclerosis, osteophyte formation and inflammation of the synovial membrane. We previously reported that OA osteoblasts (Ob) show abnormal phenotypic characteristics possibly responsible for bone sclerosis and that two subgroups of OA patients can be identified by low or high endogenous production of prostaglandin E-2 (PGE(2)) by OA Ob. Here, we determined that the elevated PGE2 levels in the high OA subgroup were linked with enhanced cyclooxygenase-2 (COX-2) protein levels compared to normal and low OA Ob. A linear relationship was observed between endogenous PGE2 levels and insulin-like growth factor I (IGF-1) levels in OA Ob. As parathyroid hormone (PTH) and PGE(2) are known stimulators of IGF-1 production in Ob, we next evaluated their effect in OA Ob. Both subgroups increased their IGF-1 production similarly in response to PGE2, while the high OA subgroup showed a blunted response to PTH compared to the low OA group. Conversely, only the high OA group showed a significant inhibition of IGF-1 production when PGE2 synthesis was reduced with Naproxen, a non-steroidal anti inflammatory drug (NSAID) that inhibits cyclooxygenases (COX). The PGE(2)-dependent stimulation of IGF-1 synthesis was due in part to the cAMP/protein kinase A pathway since both the direct inhibition of this pathway with H-89 and the inhibition of EP2 or EP4 receptors, linked to cAMP production, reduced IGF-1 synthesis. The production of the most abundant IGF-1 binding proteins (IGFBPs) in bone tissue, IGFBP-3, -4, and -5, was lower in OA compared to normal Ob independently of the OA group. Under basal condition, OA Ob expressed similar IGF-1 mRNA to normal Ob; however, PGE2 stimulated IGF-1 mRNA expression more in OA than normal Ob. These data suggest that increased IGF-1 levels correlate with elevated endogenous PGE2 levels in OA Ob and that higher IGF-1 levels in OA Ob could be important for bone sclerosis in OA. (c) 2005 Elsevier Inc. All rights reserved.