Harpagoside通过Syk-Btk-PLCγ2-Ca2 <sup>+</sup>信号通路抑制RANKL诱导的破骨细胞生成，并防止炎症介导的骨丢失,Journal of Natural Products

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Harpagoside通过Syk-Btk-PLCγ2-Ca2 ⁺信号通路抑制RANKL诱导的破骨细胞生成，并防止炎症介导的骨丢失
Journal of Natural Products ( IF 3.3 ) Pub Date : 2015-08-26 00:00:00 , DOI: 10.1021/acs.jnatprod.5b00233
Ju-Young Kim ₁ , Sun-Hyang Park ₁ , Jong Min Baek ₁ , Munkhsoyol Erkhembaatar ₁ , Min Seuk Kim ₁ , Kwon-Ha Yoon ₁ , Jaemin Oh ₁ , Myeung Su Lee ₁

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Harpagoside（HAR）是从Harpagophytum procumbens（魔爪）中分离出来的天然化合物，据报道具有抗炎作用。但是，尚未在骨骼发育的背景下研究这些作用。当前的研究首次描述了HAR在体外抑制核因子κB配体（RANKL）诱导的破骨细胞生成的受体激活剂并抑制小鼠模型中炎症引起的骨质流失。HAR还以剂量依赖性方式抑制小鼠骨髓巨噬细胞（BMM）的破骨细胞形成，以及成熟的破骨细胞的活性，包括丝状肌动蛋白（F-actin）环形成和骨基质分解。这涉及HAR诱导的细胞外信号调节激酶（ERK）和c-jun N末端激酶（JNK）磷酸化的降低，从而导致RANKL依赖的早期信号传导中Syk-Btk-PLCγ2-Ca2 ⁺的抑制，以及激活的T细胞胞质1（NFATc1）的c-Fos和核因子的激活，导致各种靶基因的下调。与这些体外一致结果，在炎性骨质疏松症模型中，HAR阻断了脂多糖（LPS）引起的骨质流失。然而，在绝经后骨质疏松症模型中，HAR并不能预防卵巢切除术介导的骨侵蚀。这些结果表明，HAR是抗炎相关骨疾病的有价值的药物，但不是由荷尔蒙异常引起的骨质疏松症的有价值的药物。

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Harpagoside Inhibits RANKL-Induced Osteoclastogenesis via Syk-Btk-PLCγ2-Ca2+ Signaling Pathway and Prevents Inflammation-Mediated Bone Loss

Harpagoside (HAR) is a natural compound isolated from Harpagophytum procumbens (devil’s claw) that is reported to have anti-inflammatory effects; however, these effects have not been investigated in the context of bone development. The current study describes for the first time that HAR inhibits receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis in vitro and suppresses inflammation-induced bone loss in a mouse model. HAR also inhibited the formation of osteoclasts from mouse bone marrow macrophages (BMMs) in a dose-dependent manner as well as the activity of mature osteoclasts, including filamentous actin (F-actin) ring formation and bone matrix breakdown. This involved a HAR-induced decrease in extracellular signal-regulated kinase (ERK) and c-jun N-terminal kinase (JNK) phosphorylation, leading to the inhibition of Syk-Btk-PLCγ2-Ca²⁺ in RANKL-dependent early signaling, as well as the activation of c-Fos and nuclear factor of activated T cells cytoplasmic 1 (NFATc1), which resulted in the down-regulation of various target genes. Consistent with these in vitro results, HAR blocked lipopolysaccharide (LPS)-induced bone loss in an inflammatory osteoporosis model. However, HAR did not prevent ovariectomy-mediated bone erosion in a postmenopausal osteoporosis model. These results suggest that HAR is a valuable agent against inflammation-related bone disorders but not osteoporosis induced by hormonal abnormalities.

更新日期：2015-08-26

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