Advanced Science
·
2025
·
IF 14.1
Wenwei Li,Yang Liu,Ming Wei,Zhichao Yang,Zhaoyu Li,Zezhong Guo,Liang Yan,Yang Lu,Hao Tang,Bofeng Li,Wei Huang
Osteoarthritis (OA) is a low-grade inflammatory disease that is highly associated with severe hyperplasia of the synovial membrane and the degeneration of cartilage. Interleukin-10 (IL-10), has been extensively studied, while its receptor, IL-10Rα, has not been widely mentioned in the context of OA. A significant difference is found in the expression of IL-10Rα in synovial macrophages from normal and OA patients, along with a marked increase in the glycolytic activity of synovial macrophages. In IL-10Rα Lysm OA mice, the specific deficiency of IL-10Rα exacerbated the progression of OA. Mechanistically, hypoxia-inducible factor-1α (HIF-1α) is identified as a key transcription factor, and its inhibition significantly weakened the glycolytic process. Additionally, differences in ferroptosis of chondrocytes are observed. After co-culturing the two types of cells in vitro, a significant connection is found between the glycolytic state of synovial macrophages and the ferroptosis of chondrocytes. To achieve targeted therapy, MI@UN, a biomimetic nanoparticle encapsulating NO-prednisolone in UIO-66-NH 2 , surface-modified with IL-10, and coated with macrophage membranes (MM), is developed. It significantly slows osteoarthritis progression in mice. This offers new insights into OA pathogenesis, highlighting IL-10Rα as a therapeutic target and supporting MI@UN's translational use for OA treatment.
研究领域:
免疫学
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骨科
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纳米医学
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产品关联
DOI
PubMed
高影响因子
Advanced Composites and Hybrid Materials
·
2025
·Vol. 8
·期 3
·1-21
·
IF 21.8
Yan Wenqiang,Tian Feng,Zhao Lingyu,Wang Pengyi,Zhang Manwen,Gao Zeyuan,Huang Wei,Ao Yingfang,Yu Ran
Three-dimensionally (3D) printed engineered meniscus scaffolds offer a promising therapeutic strategy for post-meniscectomy defects. Nevertheless, existing scaffolds face critical limitations impeding clinical implementation. Primarily, the transplantation procedure necessitates larger incisions in skin and joint capsules due to insufficient scaffold deformability. This invasive approach risks iatrogenic tissue damage, prolongs recovery timelines, and compromises aesthetic outcomes. Secondly, conventional fixation methods involving sutures to peripheral meniscal remnants or capsular tissues introduce dual complications: mechanical perforation of scaffolds reduces structural integrity and accelerates degradation, while the demanding technical requirements for suture placement increase surgical complexity. To address these challenges, we engineered a composite meniscus scaffold featuring an elastomeric skeleton fabricated via digital light processing (DLP) 3D printing integrated with a hydrogel matrix. This biomimetic design recapitulates the native meniscus architecture comprising an aqueous extracellular matrix reinforced by collagen fibrils. The composite scaffold demonstrates three critical functional attributes: 1) biomechanical properties approximating native meniscus tissue, 2) exceptional shape recovery capabilities facilitating trans-arthroscopic delivery through minimally invasive portals, and 3) strong interfacial adhesion enabling suture-free fixation via covalent bonding to host tissues. In vivo evaluation using a rabbit meniscectomy model confirmed the scaffold’s chondroprotective efficacy. Notably, preclinical validation in an ex vivo ovine knee under arthroscopic guidance demonstrated successful scaffold deployment through subcentimeter incisions with stable adhesion to residual meniscal tissue. This innovative design eliminates suture-related complications while reducing surgical invasiveness, thereby presenting a clinically translatable solution for irreparable meniscal injuries.
研究领域:
生物医学工程
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再生医学
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骨科
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产品关联
DOI
高影响因子
BIOMATERIALS
·
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
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产品关联
DOI
PubMed
高影响因子
AGING CELL
·
2024
·Vol. 23
·期 3
·e14053
·
IF 8
Ying Huai,Xue Wang,Wenjing Mao,Xuehao Wang,Yipu Zhao,Xiaohua Chu,Qian Huang,Kang Ru,Ling Zhang,Yu Li,Zhihao Chen,Airong Qian
Aging impairs osteoblast function and bone turnover, resulting in age-related bone degeneration. Stress granules (SGs) are membrane-less organelles that assemble in response to stress via the recruitment of RNA-binding proteins (RBPs), and have emerged as a novel mechanism in age-related diseases. Here, we identified HuR as a bone-related RBP that aggregated into SGs and facilitated osteogenesis during aging. HuR-positive SG formation increased during osteoblast differentiation, and HuR overexpression mitigated the reduction in SG formation observed in senescent osteoblasts. Moreover, HuR positively regulated the mRNA stability and expression of its target β-catenin by binding and recruiting β-catenin into SGs. As a potential therapeutic target, HuR activator apigenin (API) enhanced its expression and thus aided osteoblasts differentiation. API treatment increased HuR nuclear export, enhanced the recruitment of β-catenin into HuR-positive SGs, facilitated β-catenin nuclear translocation, and contributed osteogenesis. Our findings highlight the roles of HuR and its SGs in promoting osteogenesis during skeletal aging and lay the groundwork for novel therapeutic strategies against age-related skeletal disorders.
研究领域:
老年学
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分子生物学
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骨生物学
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DOI
PubMed
高影响因子
Cell Communication and Signaling
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2024
·Vol. 22
·期 1
·1-14
·
IF 8.2
Liu Haixia,Huang Renhuan,Zhuo Ziang,Zhang Xinru,Wu Ling,Guo Zhen,Wen Fuping,An Liwei,Yuan Hang,Zhang Yiming,Xu Yuanzhi
Objective Kappa opioid receptor (KOR) signaling is involved in joint development and inflammation in Osteoarthritis (OA), while the biochemical mechanism remains unclarified. This study aims to investigate downstream molecular events of KOR activation, to provide novel perspectives in OA pathology. Methods U50,488H, a selective KOR agonist, was intra-articularly injected in mice upon destabilization of the medial meniscus (DMM) as OA models, with PBS injection as control. The behavioral and histological evaluation was assessed by hot plate test and red solid green staining, respectively. Alterations in mRNA and protein expression were assessed by RNA-seq, RT-qPCR, immunohistochemistry and western blotting (WB) in chondrocytes treated with TNF-α or TNF-α + U50,488H. Proteins interacted with KOR were explored using proximity labeling followed by mass spectrometry and then testified by co-immunoprecipitation (Co-IP) assay and immunofluorescence (IF). Results OA-induced pain was reduced and cartilage degeneration was alleviated upon KOR activation in DMM mice. In chondrocytes, activation of KOR reversed the upregulation of MMPs, IL-6, IL-1β and phosphorylated(p-) STAT3, stimulated by TNF-α, while the expression of NF-κB, MAPKs and AKT signaling weren't reversed. RNA-seq and IF results presented that KOR activation evidently reduced STAT3 nuclear translocation in chondrocytes upon TNF-α stimuli. The reduction may be resulted from the binding of KOR and STAT3 in the plasma membrane, revealed by proximity labeling and Co-IP results. Conclusions KOR activation protects cartilage from OA, and this protective effect is mainly exerted via sequestering STAT3 on the plasma membrane, resulting in inactivation of STAT3-dependent immune responses which otherwise contributes to OA.
研究领域:
药理学
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骨科
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分子生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2024
·
IF 5.3
Cheng-Ming Zhang,Yu-Xin Kang,Si-Yu Zheng,Yang Liu,Meng-Rou Liu,Gai-Ge Wu,Li Guo,Peng-Cui Li,Rui-Peng Zhao,Qian-Qian Duan,Shao-Wei Wang,Xiao-Chun Wei
Background Osteoarthritis (OA) is a progressive joint disorder marked by the degradation of cartilage. Elevated concentrations of hypoxia-inducible factor-2α (HIF-2α) are intricately linked to the pathological development of OA. PT2385 has demonstrated effective inhibition of HIF-2α, thereby potentially impeding the initial advancement of OA. Nevertheless, challenges persist, including limited penetration into the deeper layers of cartilage, issues related to charge rejection, and a heightened rate of clearance from the joint. These constraints necessitate further consideration and exploration. Methods It has been demonstrated that PT2385 exhibits efficient inhibition of HIF-2α expression, thereby contributing to the delay in the progression of osteoarthritis. The pH-responsive attributes of carbon quantum dots, specifically those employing m-phenylenediamine (m-CQDs) coated with bovine serum albumin (BSA), have been systematically evaluated. In both in vitro settings involving cartilage explants and in vivo experiments, the efficacy of BSA-m-CQDs-PT2385 (BCP) has been confirmed in facilitating the transport of PT2385 to the middle and deep layers of cartilage. Furthermore, the BCP system demonstrates controlled drug release contingent upon alterations in environmental pH. Results While the use of PT2385 alone provides protective effects on chondrocytes within an inflamed environment, there exists an opportunity for further enhancement in its efficacy when administered via intra-articular injection. The BCP formulation, characterized by appropriate particle size and charge, facilitates seamless penetration into cartilage tissue. Additionally, BCP demonstrates the capability to release drugs in response to changes in environmental pH. In vitro experiments reveal that BCP effectively inhibits Hif-2α expression and catabolic factors in chondrocytes. Notably, cartilage explants and in vivo experiments indicate that BCP surpasses PT2385 alone in inhibiting the expression of HIF-2α and matrix metalloproteinase 13, particularly in the middle and deep layers. Conclusions The BCP drug delivery system exhibits selective release of PT2385 in response to pH changes occurring during the progression of osteoarthritis (OA), thereby inhibiting HIF-2α expression deep within the cartilage. The use of BCP significantly augments the capacity of PT2385 to retard both cartilage degeneration and the progression of osteoarthritis. Consequently, BCP as an innovative approach utilizing m-CQDs to deliver PT2385 into articular cartilage, shows potential for treating osteoarthritis. This strategy opens new avenues for osteoarthritis treatment.
研究领域:
药学
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生物医学工程
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骨科
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cartilage
·
2021
·
IF 4.634
Zhaoxun Chen,Chen Zhao,Pengcheng Liu,Haohan Huang,Shuhong Zhang,Xiaoqing Wang
ObjectiveEmerging evidence has indicated that excessive reactive oxygen species (ROS) have detrimental effects on osteoarthritis (OA). This study aimed to elucidate the effects of melatonin (MT), an antioxidant indolamine secreted from the pineal gland, on chondrocyte senescence and cartilage degeneration, thereby clarifying the underlying mechanisms of ROS-induced OA pathogenesis.DesignHydrogen peroxide (H2O2) was used to induce oxidative stress in rat chondrocytes. ROS levels were evaluated using cytometry and immunofluorescence. Cell viability was detected using the Cell Counting Kit-8 (CCK-8) assay. Western blotting and qPCR (Quantiative Real-Time Polymerase Chain Reaction) were used to examine apoptosis and autophagy. For in vivo experiments, male Sprague-Dawley rats were randomly divided into a sham-operated group, DMM (destabilization of the medial meniscus) surgery group, and surgery groups that received melatonin. Knee joints were collected and stained for histological analysis.ResultsThe data demonstrated that melatonin treatment significantly suppressed H2O2-induced matrix degradation and apoptosis, and maintained mitochondrial redox homeostasis. In addition, an enhancement of autophagic flux was observed through western blotting. These findings corresponded with activation of the AMPK/Foxo3 signaling pathways upon melatonin treatment. Histological staining and transmission electron microscopy (TEM) micrographs also demonstrated that melatonin alleviated cartilage ossification and chondrocyte hypertrophy in vivo.ConclusionsOur results indicated that melatonin protected chondrocytes via mitochondrial redox homeostasis and autophagy. The effects of melatonin on senescence may apply to other age-related diseases. Thus, melatonin may have multiple potential therapeutic applications.
研究领域:
药理学
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细胞生物学
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风湿病学
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骨科
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产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2021
·Vol. 9
·期 22
·7603-7616
·
IF 6.843
Wei Yu,Bin Hu,Kofi Oti Boakye-Yiadom,William Ho,Qijing Chen,Xiaoyang Xu,Xue-Qing Zhang
Osteoarthritis (OA), a chronic and degenerative joint disease, remains a challenge in treatment due to the lack of disease-modifying therapies. As a promising therapeutic agent, adipose-derived stem cells (ADSCs) have an effective anti-inflammatory and chondroprotective paracrine effect that can be enhanced by genetic modification. Unfortunately, direct cell delivery without matrix support often results in poor viability of therapeutic cells. Herein, a hydrogel implant approach that enabled intra-articular delivery of gene-engineered ADSCs was developed for improved therapeutic outcomes in a surgically induced rat OA model. An injectable extracellular matrix (ECM)-mimicking hydrogel was prepared as the carrier for cell delivery, providing a favorable microenvironment for ADSC spreading and proliferation. The ECM-mimicking hydrogel could reduce cell death during and post injection. Additionally, ADSCs were genetically modified to overexpress transforming growth factor-β1 (TGF-β1), one of the paracrine factors that exert an anti-inflammatory and pro-anabolic effect. The gene-engineered ADSCs overexpressing TGF-β1 (T-ADSCs) had an enhanced paracrine effect on OA-like chondrocytes, which effectively decreased the expression of tumor necrosis factor-alpha and increased the expression of collagen II and aggrecan. In a surgically induced rat OA model, intra-articular injection of the T-ADSC-loaded hydrogel markedly reduced cartilage degeneration, joint inflammation, and the loss of the subchondral bone. Taken together, this study provides a potential biomaterial strategy for enhanced OA treatment by delivering the gene-engineered ADSCs within an ECM-mimicking hydrogel.
研究领域:
再生医学
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干细胞治疗
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骨科
✓ 已验证
DOI
PubMed
高影响因子
Advanced Science
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2025
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IF 14.1
Caifeng Deng,Yongbing Xiao,Xuan Zhao,Hui Li,Yuxiao Chen,Kelong Ai,Ting Jiang,Jie Wei,Xiaoyuan Chen,Guanghua Lei,Chao Zeng
The infiltration and excessive polarization of M1 macrophages contribute to the induction and persistence of low-grade inflammation in joint-related degenerative diseases such as osteoarthritis (OA). The lipid metabolism dysregulation promotes M1 macrophage polarization by coordinating the compensatory pathways of the inflammatory and oxidative stress responses. Here, a self-assembling, licofelone-loaded nanoparticle (termed LCF-CSBN), comprising chondroitin sulfate and bilirubin joined by an ethylenediamine linker, is developed to selectively reprogram lipid metabolism in macrophage activation. LCF-CSBN is internalized by M1 macrophages via CD44-mediated endocytosis and targets the Golgi apparatus accompanied with the reactive oxygen species-responsive release of licofelone (LCF, dual inhibitor of arachidonic acid metabolism). LCF-CSBN effectively promotes M1 to M2 macrophage transition by reprogramming the Golgi apparatus-related sphingolipid metabolism and arachidonic acid metabolism. Intra-articularly injected LCF-CSBN retains in the joint for up to 28 days and accumulates into M1 macrophages. Moreover, LCF-CSBN can effectively attenuate joint inflammation, oxidative stress, and cartilage degeneration in OA model rats. These findings indicate the promising potential of lipid-metabolism-reprogramming LCF-CSBN in the targeted therapy of OA.
研究领域:
药理学
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免疫学
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骨科
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纳米技术
·
代谢
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
·
2017
·Vol. 40
·期 6
·1709-1718
·
IF 2.341
Baochao Ji,Wentao Guo,Hairong Ma,Boyong Xu,Wenbo Mu,Zhendong Zhang,Abdusami Amat,Li Cao
Isoliquiritigenin (ISL), a natural flavonoid extracted from licorice, has been demonstrated to exert attenuation of the nuclear factor-κB (NF-κB) signaling pathway and anti-inflammatory activity in a wide variety of cells. In the present study, the authors first evaluated the effects of ISL on cartilage degeneration in interleukin-1β (IL-1β)-stimulated chondrocyte-like ATDC5 cells and in a mouse model of osteoarthritis (OA). The data of a cell counting kit-8 and flow cytometry assay indicated that ISL suppressed the inhibitory effect of IL-1β on cell viability. The mRNA and protein expression levels of cyclooxygenase-2 and matrix metalloproteinase-13 were significantly decreased, while the expression of collagen II was increased, as indicated by RT-qPCR and western blot analysis following the chondrocyte-like ATDC5 cells were co-intervened with IL-1β and ISL for 48 h. Also, ISL attenuated protein expressions level of pro-apoptotic Bax, cleaved-caspase-3 and cleaved-caspase-9 and promoted expression of anti-apoptotic Bcl-2. Moreover, ISL inhibited NF-κB p65 phosphorylation induced by IL-1β. In addition, ISL also increased improved the thickness of hyaline cartilage and the production of proteoglycans in the cartilage matrix in a mouse OA model. These results indicated that ISL exerted anti-inflammatory and anti-apoptotic effects on IL-1β-stimulated chondrocyte-like ATDC5 cells, which may be associated with the downregulation of the NF-κB signaling pathway. In this way, the data supported the conclusion that ISL may be a novel potential preventive agent suitable for use in OA therapy.
研究领域:
药理学
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风湿病学
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分子生物学
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细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
Small
·
2024
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IF 13
Hongtao Zhang,Shiguo Yuan,Boyuan Zheng,Peng Wu,Xiuming He,Yi Zhao,Zhangfeng Zhong,Xiaofang Zhang,Jian Guan,Huajun Wang,Lei Yang,Xiaofei Zheng
Osteoarthritis (OA) is a progressively developing condition primarily characterized by the deterioration of articular cartilage and the proliferation of bone, along with ongoing inflammation. Although the precise pathogenesis remains somewhat elusive, restoring the homeostatic balance of the intra-articular microenvironment is crucial for the management of OA. Intra-articular injection of medication is one of the most direct and effective treatment methods; however, most injectable drugs used for osteoarthritis treatment, due to their rapid breakdown, quick release, poor biological activity, and frequent injections, leading to increased risk of infection and suboptimal therapeutic outcomes. In this study, a lubricating and dual-responsive injectable hydrogel based on zeolitic imidazolate frameworks-8 (ZIF-8) impregnated with Quercetin (Que) is designed, which can facilitate OA treatment by remodeling the microenvironment. The prepared injectable nanocomposite hydrogel (MH/CCM@ZIF-8@Que) exhibits pH and reactive oxygen species (ROS) responsiveness, alongside a controllable release of bioactive substances to modulate the microenvironment of bone tissue, thereby mitigating synovitis and the degeneration of cartilage matrix, while simultaneously facilitating cartilage repair. This developed thermosensitive injectable hydrogel, which effectively balances lubrication with the controlled release of bioactive substances, represents a highly promising therapeutic approach for osteoarthritis.
研究领域:
药学
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材料科学
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生物医学工程
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骨科
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOLOGICAL TRACE ELEMENT RESEARCH
·
2019
·Vol. 193
·期 2
·422-433
·
IF 2.431
Hu Peilin,Du Jie,Zhang Shuai,Wang Ting,Li Jun,Chen Gang,Zhou Guangqian
Osteoarthritis (OA), a common degenerative disease affecting articular cartilage, is caused by multiple factors, and currently, there are few approaches to effectively delay its progression. This study aimed to evaluate whether a strontium compound (in the form of strontium gluconate, Glu-Sr) could reduce OA pathology severity in osteoarthritic rat models by directly targeting chondrocytes, including catabolic/anabolic activities and/or chondrogenic differentiation. Glu-Sr was administered to OA rats by oral gavage beginning during OA induction and continuing for 8 weeks. Glu-Sr treatment was found to significantly reduce cartilage degeneration and delay OA progression. Further examination showed that collagen II, Sox9, and aggrecan (ACAN) genes were up-regulated whereas IL-1β was down-regulated in chondrocytes isolated from Glu-Sr-treated rats. Glu-Sr also antagonized the catabolic effects of IL-1β on chondrocytes. Furthermore, Glu-Sr was shown to promote the chondrogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs), possibly through promoting chondrogenic gene expression, including CTGF and FGF1, as revealed by RNA-sequencing (RNA-seq). These results suggest that systemic administration of Glu-Sr may be useful in prophylactic and therapeutic treatment of chronic cartilage degradation through affecting multiple steps from chondrogenic differentiation of progenitors to matrix formation in mature chondrocytes.
研究领域:
风湿病学
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骨科
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分子生物学
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干细胞研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）