Prolactin blocks the expression of receptor activator of nuclear factor κB ligand and reduces osteoclastogenesis and bone loss in murine inflammatory arthritis.
Prolactin blocks the expression of receptor activator of nuclear factor κB ligand and reduces osteoclastogenesis and bone loss in murine inflammatory arthritis.
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DOI：
10.1186/s13075-017-1290-4
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发表时间：
2017-05-15
影响因子：
4.9
通讯作者：
Clapp C
中科院分区：
文献类型：
--
作者：
Ledesma-Colunga MG;Adán N;Ortiz G;Solís-Gutiérrez M;López-Barrera F;Martínez de la Escalera G;Clapp C
催乳素（PRL）可减少多关节炎性关节炎（AIA）大鼠的关节炎症、血管翳形成和骨破坏。在这里，我们调查的机制，催乳素保护骨丢失在AIA和单关节AIA（马亚）。在接受PRL（通过渗透性微型泵）治疗的AIA大鼠和PRL受体无效（Prlr-/-）或无效（Prlr+/+）的马亚小鼠中评价关节炎症、骨小梁丢失和破骨细胞生成。为了帮助确定靶细胞，用促炎细胞因子（（Cyt），包括TNFα、IL-1β和干扰素（IFN）γ）（含或不含PRL）处理或不处理来自Prlr+/+小鼠的滑膜成纤维细胞，并将这些滑膜细胞与来自Prlr+/+或Prlr-/-小鼠的骨髓破骨细胞祖细胞共培养或不共培养。在AIA中，PRL治疗减轻了关节肿胀，增加了骨小梁面积，降低了破骨细胞密度，并降低了破骨细胞相关基因的mRNA水平（抗酒石酸酸性磷酸酶（Trap））、组织蛋白酶K（Ctsk）、基质金属蛋白酶9（Mmp 9）和核因子κB或RANK的受体激活剂（Tnfrsf 11 a）），编码具有破骨细胞生成活性的细胞因子的基因（Tnfa、IL 1 B、IL 6和核因子κB配体或RANKL的受体激活剂（Tnfrsf 11）），以及编码与辅助性T（Th）17细胞（Rora、Rorc、Il 17 a、Il 21、Il 22）和调节性T细胞（Foxp 3、Ebi 3、Il 12 a、Tgfb 1、Il 10）相关的转录因子和细胞因子的基因。患有马亚的Prlr-/-小鼠显示关节肿胀增强、骨小梁面积减少、破骨细胞密度增加以及Tnfa、Illb、Il 6、Trap、Tnfrsf 11 a、Tnfrsf 11、Il 17 a、Il 21、Il 22、Il 23、Foxp 3和Il 10的表达升高。长PRL受体形式的表达增加关节炎关节，滑膜和培养的滑膜成纤维细胞与细胞色素治疗。PRL诱导滑膜成纤维细胞培养物中信号转导和转录激活因子3（STAT 3）的磷酸化/激活，并抑制细胞诱导的IL 1b、IL 6和Tnfrsf 11的表达。STAT 3抑制剂S31-201可阻断PRL对Tnfrsf 11的抑制作用。最后，PRL作用于滑膜成纤维细胞和破骨细胞前体细胞，下调细胞诱导的破骨细胞分化。PRL通过其经典的STAT 3信号通路抑制关节和滑膜成纤维细胞中马槟榔碱诱导的RANKL表达，从而保护炎症性关节炎中的破骨细胞生成和骨丢失。本文的在线版本（doi：10.1186/s13075-017-1290-4）包含补充材料，可供授权用户使用。
Prolactin (PRL) reduces joint inflammation, pannus formation, and bone destruction in rats with polyarticular adjuvant-induced arthritis (AIA). Here, we investigate the mechanism of PRL protection against bone loss in AIA and in monoarticular AIA (MAIA). Joint inflammation, trabecular bone loss, and osteoclastogenesis were evaluated in rats with AIA treated with PRL (via osmotic minipumps) and in mice with MAIA that were null (Prlr-/-) or not (Prlr+/+) for the PRL receptor. To help define target cells, synovial fibroblasts from Prlr+/+ mice were treated or not with proinflammatory cytokines ((Cyt), including TNFα, IL-1β, and interferon (IFN)γ) with or without PRL, and these synovial cells were co-cultured or not with bone marrow osteoclast progenitors from Prlr+/+ or Prlr-/- mice. In AIA, PRL treatment reduced joint swelling, increased trabecular bone area, lowered osteoclast density, and reduced mRNA levels of osteoclast-associated genes (tartrate-resistant acid phosphatase (Trap)), cathepsin K (Ctsk), matrix metalloproteinase 9 (Mmp9), and receptor activator of nuclear factor κB or RANK (Tnfrsf11a)), of genes encoding cytokines with osteoclastogenic activity (Tnfa, Il1b, Il6, and receptor activator of nuclear factor κB ligand or RANKL (Tnfrsf11)), and of genes encoding for transcription factors and cytokines related to T helper (Th)17 cells (Rora, Rorc, Il17a, Il21, Il22) and to regulatory T cells (Foxp3, Ebi3, Il12a, Tgfb1, Il10). Prlr-/- mice with MAIA showed enhanced joint swelling, reduced trabecular bone area, increased osteoclast density, and elevated expression of Tnfa, Il1b, Il6, Trap, Tnfrsf11a, Tnfrsf11, Il17a, Il21, Il22, 1 l23, Foxp3, and Il10. The expression of the long PRL receptor form increased in arthritic joints, and in synovial membranes and cultured synovial fibroblasts treated with Cyt. PRL induced the phosphorylation/activation of signal transducer and activator of transcription-3 (STAT3) and inhibited the Cyt-induced expression of Il1b, Il6, and Tnfrsf11 in synovial fibroblast cultures. The STAT3 inhibitor S31-201 blocked inhibition of Tnfrsf11 by PRL. Finally, PRL acted on both synovial fibroblasts and osteoclast precursor cells to downregulate Cyt-induced osteoclast differentiation. PRL protects against osteoclastogenesis and bone loss in inflammatory arthritis by inhibiting cytokine-induced expression of RANKL in joints and synovial fibroblasts via its canonical STAT3 signaling pathway. The online version of this article (doi:10.1186/s13075-017-1290-4) contains supplementary material, which is available to authorized users.