Nangibotide attenuates osteoarthritis by inhibiting osteoblast apoptosis and TGF-β activity in subchondral bone
Nangibotide attenuates osteoarthritis by inhibiting osteoblast apoptosis and TGF-β activity in subchondral bone
复制标题
Nangibotide 通过抑制软骨下骨中的成骨细胞凋亡和 TGF-β 活性来减轻骨关节炎
DOI：
10.1007/s10787-022-00984-2
复制
发表时间：
2022
影响因子：
5.8
通讯作者：
Jinzhong Ma
中科院分区：
文献类型：
--
作者：
Yiming Zhong;Yiming Xu;Song Xue;Libo Zhu;Haiming Lu;Cong Wang;Hongjie Chen;Weilin Sang;Jinzhong Ma
骨关节炎（OA）是一种慢性关节疾病，导致软骨退化和软骨下骨异常。Nangibotide，也称为LR 12，是一种具有相当抗炎特性的十二肽，但其在OA中的意义尚不确定。本研究的目的是确定nangibotide是否可以减缓OA的进展，并阐明其潜在的机制。体外实验表明，nangibotide可明显抑制TNF-α诱导的成骨细胞减少，显著促进成骨细胞增殖，并抑制MC 3 T3-E1细胞凋亡。将2月龄雄性C57 BL/6 J小鼠随机分为3组：假手术组、ACLT组和ACLT + nangibotide治疗组。Nangibotide抑制ACLT诱导的软骨降解和MMP-13表达。MicroCT分析显示，nangibotide可减轻ACLT诱导的体内软骨下骨丢失。组织形态计量学结果显示nangibotide减弱ACLT诱导的成骨细胞抑制; TUNEL法和裂解型半胱天冬酶3免疫组化染色进一步证实了nangibotide对成骨细胞的体内抗凋亡作用。此外，我们发现nangibotide通过抑制Smad 2/3介导的TGF-β信号传导来恢复软骨下骨的偶联骨重建，从而发挥保护作用。总之，研究结果表明，nangibotide可能对骨软骨单位产生保护作用，并可能成为OA的替代治疗选择。
Osteoarthritis (OA) is a chronic joint disorder that causes cartilage degradation and subchondral bone abnormalities. Nangibotide, also known as LR12, is a dodecapeptide with considerable anti-inflammatory properties, but its significance in OA is uncertain. The aim of the study was to determine whether nangibotide could attenuate the progression of OA, and elucidate the underlying mechanism. In vitro experiments showed that nangibotide strongly inhibited TNF-α-induced osteogenic reduction, significantly enhanced osteoblast proliferation and prevented apoptosis in MC3T3-E1 cells. Male C57BL/6 J mice aged 2 months were randomly allocated to three groups: sham, ACLT, and ACLT with nangibotide therapy. Nangibotide suppressed ACLT-induced cartilage degradation and MMP-13 expression. MicroCT analysis revealed that nangibotide attenuated in vivo subchondral bone loss induced by ACLT. Histomorphometry results showed that nangibotide attenuated ACLT-induced osteoblast inhibition; TUNEL assays and immunohistochemical staining of cleaved-caspase3 further confirmed the in vivo anti-apoptotic effect of nangibotide on osteoblasts. Furthermore, we found that nangibotide exerted protective effects by suppressing TGF-β signaling mediated by Smad2/3 to restore coupled bone remodeling in the subchondral bone. In conclusion, the findings suggest that nangibotide might exert a protective effect on the bone-cartilage unit and maybe an alternative treatment option for OA.