BIOMATERIALS
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2014
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IF 8.312
Pengfei Chen,Shouan Zhu,Yanyan Wang,Qin Mu,Yan Wu,Qingqing Xia,Xiaolei Zhang,Heng Sun,Jiadong Tao,Hu Hu,Ping Lu,Hongwei Ouyang
Degradation of proteoglycan is the key early event in the development of osteoarthritis (OA). The aggrecanase ADAMTS-5 has been identified as the major enzyme responsible for the degradation and thus is an attractive therapeutic target for OA. However, currently there is no report on using an ADAMTS-5 inhibition strategy for OA treatment. The present study aimed to investigate the synergic effect of combining an ADAMTS-5 inhibitor (114810) with a hyaluronic acid hydrogel (HAX) for OA therapeutics. Two OA models were induced by surgically creating an osteochondral defect or removing the anterior cruciate ligament (ACL) in Sprague–Dawley rats. Human OA cartilage was obtained from total joint replacement patients. Both human and rat OA cartilage showed marked proteoglycan loss with significantly increased ADAMTS-5 expression. The effectiveness of ADAMTS-5 inhibition by 114810 was confirmed by a cartilage explants assay in vitro , which showed that the 114810 halted the aggrecanase-mediated 374 ARGS neoepitope released from aggrecan induced by IL-1β stimulation. The in vivo effect of ADAMTS-5 inhibition was assessed by the articular injection of HAX with 114810 into OA knee joints. Evaluated eight weeks after injection, 114810 with HAX significantly promoted the in vivo cartilage healing in the osteochondral defect model, and prevented the progression of degenerative changes in the ACL model. Our results confirmed that ADAMTS-5 is an effective target for OA treatment, and the intra-articular injection of an ADAMTS-5 inhibitor within HAX gel could be a promising strategy for OA treatment.
研究领域:
骨科
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药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food & Function
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2020
·Vol. 11
·期 12
·10852-10863
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IF 4.171
Mingbao Gu,Jie Jin,Chenghao Ren,Ximiao Chen,Weiyang Gao,Xiangyang Wang,Yaosen Wu,Naifeng Tian,Zongyou Pan,Aimin Wu,Yifei Zhou,Xiaolei Zhang
As an ordinary joint vestigial disease, osteoarthritis (OA) contributes to a considerable proportion of disability cases worldwide. Inflammation, as the main pathological factor, mediates the occurrence and development of OA. Akebia Saponin D (ASD), also known as Asperosaponin VI, is one of the active components extracted from Dipsaci Radix and is rich in Dipsacus loose tea. It has shown sound therapeutic effects on various diseases; nevertheless, its role in OA therapy is not completely understood. This study demonstrated the anti-inflammatory activity of ASD in OA through a series of in vivo and in vitro experiments. In vitro experiments revealed that ASD might prohibit the production of inflammatory mediators in IL-1β treated chondrocytes such as COX-2, iNOS, NO, PGE2, IL-6, and TNF-α. Meanwhile, it may also inhibit the production of ADAMTS-5 and MMP13 and promote the production of Aggrecan and Collagen II. The mechanism study demonstrated that ASD exerted an anti-inflammatory effect by activating the NRF2 target, upregulating the expression of HO-1, and preventing P65 from binding to DNA. In vivo experiments demonstrated that ASD might improve the progression of OA in a DMM mouse model. These research results provide evidence for the potential application of ASD in OA therapy.
研究领域:
药理学
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风湿病学
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炎症研究
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骨科
✓ 已验证
DOI
PubMed
高影响因子
INFLAMMATION
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2024
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IF 4.5
Liu Yadong,Zhang Guiqi,Wu Jiani,Meng Yi,Hu Jianyu,Fu Hao,Yang Dongfang
Intervertebral disc degeneration (IDD) diseases are common and frequent diseases in orthopedics. The caspase recruitment domain (CARD) and membrane-associated guanylate kinase-like protein 3 (CARMA3) is crucial in the activation of the NF-κB pathway. However, the biological function of CARMA3 in IDD remains unknown. Here, CARMA3 expression was elevated in nucleus pulposus (NP) tissues of IDD rats and nutrient deprivation (ND)-induced NP cells. The main pathological manifestations observed in IDD rats were shrinkage of the NP, reduction of NP cells, fibrosis of NP tissues, and massive reduction of proteoglycans. These changes were accompanied by a decrease in the expression of collagen II and aggrecan, an increase in the expression of the extracellular matrix (ECM) catabolic proteases MMP-3, MMP-13, and metalloprotease with ADAMTS-5, and an increase in the activity of the pro-apoptotic protease caspase-3. The expression of p-IκBα Ser32/36 and p-p65 Ser536 was also upregulated. However, these effects were reversed with the knockdown of CARMA3. Mechanistically, CARMA3 bound to BCL10 and MALT1 to form a signalosome. Knockdown of CARMA3 reduced the CARMA3-BCL10-MALT1 signalosome-mediated NF-κB activation. CARMA3 activated the NF-κB signaling pathway in a manner that bound to BCL10 and MALT1 to form a signalosome, which affects NP cell damage and is involved in the development of IDD. This supports CARMA3-BCL10-MALT1-NF-κB as a promising targeting axis for the treatment of IDD.
研究领域:
骨科
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分子生物学
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细胞生物学
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病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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