Activation of Interleukin-1 Signaling Cascades in Normal and Osteoarthritic Articular Cartilage

Fan, Zhiyong; Söder, Stephan; Oehler, S; Fundel, Katrin; Aigner, Thomas

doi:10.2353/ajpath.2007.061083

Cited by 122 publications

(103 citation statements)

References 42 publications

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“…Whereas inhibition of Rho/ROCK activation by TGFa prevents changes in chondrocyte shape, MEK/ERK signaling inhibition rescues the suppression of ECM gene expression and SOX9. Our results align with previous studies that have described roles for MEK/ERK signaling in articular cartilage degeneration 19,20,48 and point to a similar role for Rho/ROCK. This report also adds to the growing body of evidence indicating that inappropriate activation of the EGFR leads to cartilage degradation.…”

Section: Discussionsupporting

confidence: 82%

“…18 Furthermore, MEK/ERK and p38 MAPK (mitogen-activated protein kinase) signaling are implicated in the degenerative processes in articular cartilage. 19,20 Therefore, we hypothesized that these pathways also mediate TGFa signaling in articular chondrocytes and the induction of cartilage degradation. The results of our study show that TGFa activates several intracellular pathways including RhoA/ROCK and MEK/ERK and that each pathway mediates specific aspects of the cartilage response to TGFa.…”

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confidence: 99%

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Rho/ROCK and MEK/ERK activation by transforming growth factor-α induces articular cartilage degradation

Appleton

Usmani

Mort

et al. 2010

Laboratory Investigation

106

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Identification and characterization of therapeutic targets for joint conditions, such as osteoarthritis (OA), is exceedingly important for addressing the increasing burden of disease. Transforming growth factor-a (TGFa) is upregulated by articular chondrocytes in experimentally induced and human OA. To test the potential involvement of TGFa, which is an activator of epidermal growth factor receptor (EGFR) signaling, in joint degeneration and to identify signaling mechanisms mediating articular chondrocyte responses to TGFa, rat chondrocytes and osteochondral explants were treated with TGFa and various inhibitors of intracellular signaling pathways. Stimulation of EGFR signaling in articular chondrocytes by TGFa resulted in the activation of RhoA/ROCK (Rho kinase), MEK (MAPK/ERK kinase)/ERK (extracellularsignal-regulated kinase), PI3K (phosphoinositide 3-kinase) and p38 MAPK (mitogen-activated protein kinase) pathways. Modification of the chondrocyte actin cytoskeleton was stimulated by TGFa, but inhibition of only Rho or ROCK activation prevented morphological changes. TGFa suppressed expression of anabolic genes including Sox9, type II collagen and aggrecan, which were rescued only by inhibiting MEK/ERK activation. Furthermore, catabolic factor upregulation by TGFa was prevented by ROCK and p38 MAPK inhibition, including matrix metalloproteinase-13 and tumor necrosis factor-a, which are well known to contribute to cartilage digestion in OA. To assess the ability of TGFa to stimulate degradation of mature articular cartilage, type II collagen and aggrecan cleavage fragments were analyzed in rat osteochondral explants exposed to exogenous TGFa. Normal articular cartilage contained low levels of both cleavage fragments, but high levels were observed in the cartilage treated with TGFa. Selective inhibition of MEK/ERK and Rho/ROCK activation greatly reduced or completely prevented excess type II collagen and aggrecan degradation in response to TGFa. These data suggest that TGFa is a strong stimulator of cartilage degradation and that Rho/ROCK and MEK/ERK signaling have critical roles in mediating these effects. KEYWORDS: articular cartilage; chondrocyte; epidermal growth factor receptor; osteoarthritis; transforming growth factor alpha Osteoarthritis (OA) is a chronic, degenerative, synovial joint condition, which affects the knees, hips and other smaller joints of B10% of the North American population. The societal burden of OA is increasing and OA already accounts for 25% of visits to primary care physicians and for 50% of nonsteroidal anti-inflammatory drug prescriptions.1,2 Approximately 80% of individuals have radiographic evidence of OA by age 65 years, of which 60% are symptomatic.1 Furthermore, progressive joint degeneration combined with an inherently low capacity for articular cartilage regeneration makes treatment very difficult. As current therapies are strictly palliative, identification and characterization of therapeutic targets is exceedingly important to meet the increasing burden of disease. Althou...

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Section: Discussionsupporting

confidence: 82%

mentioning

confidence: 99%

Rho/ROCK and MEK/ERK activation by transforming growth factor-α induces articular cartilage degradation

Appleton

Usmani

Mort

et al. 2010

Laboratory Investigation

106

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“…Before drawing conclusions regarding the role of these proteases in the development of posttraumatic OA, these patients will need to be followed over time to evaluate if these MMPs and aggrecan degradation are more strongly correlated with the ultimate development of posttraumatic OA. Prior studies have suggested various cell-signaling mechanisms that may play a role in the development of posttraumatic OA including transforming growth factor-b, endothelin-1, interleukin-1b, and NF-jB [12,15,22,33,37,38]. Our current study should draw attention to the postinjury presence of MMPs and aggrecan degradation as potentially playing a role in progression to OA as well.…”

Section: Discussionmentioning

confidence: 99%

Intraarticular Matrix Metalloproteinases and Aggrecan Degradation Are Elevated After Articular Fracture

Haller

Swearingen

Partridge

et al. 2015

Clin Orthop Relat Res

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Background Posttraumatic osteoarthritis (OA) is a variant of OA that can develop after articular injury. Although the mechanism(s) of posttraumatic OA are uncertain, the presence and impact of postinjury proteolytic enzymes on articular cartilage remain unknown. To our knowledge, there are no studies that evaluate the presence of matrix metalloproteinases (MMPs) or aggrecan degradation after articular fracture.Questions/purposes (1) Are MMP concentrations and aggrecan degradation elevated after intraarticular fracture? (2) Are MMP concentrations and aggrecan degradation greater in high-energy injuries compared with low-energy injuries? (3) Do the concentrations of these biomarkers remain elevated at a secondary aspiration? Methods Between December 2011 and June 2013, we prospectively enrolled patients older than 18 years of age with acute tibial plateau fracture. Exclusion criteria included age older than 60 years, preexisting knee OA, injury greater than 24 hours before evaluation, contralateral knee injury, history of autoimmune disease, open fracture, and non-English-speaking patients. During the enrollment period, we enrolled 45 of the 91 (49%) tibial plateau fractures treated at our facility. Knee synovial fluid aspirations were obtained from both the injured and uninjured knees; two patients received aspirations in the emergency department and the remaining patients received aspirations in the operating room. Twenty patients who underwent spanning external fixator followed by definitive fixation were aspirated during both surgical procedures. MMP-1, -2, -3, -7, -9, -10, -12, and -13 concentrations were quantified using multiplex assays. Aggrecan degradation was quantified using sandwich enzyme-linked immunosorbent assay. Results There were higher concentrations of MMP-1 (3.89 ng/mL [95% confidence interval {CI}, 2.37-6.37] versus 0.37 ng/mL [95% CI, 0.23-0.61], p \ 0.001), MMP-3The institution of one or more of the authors (JMH, TFH) has received peer-reviewed research grant funding from the Orthopedic Trauma Association, LS Peery Foundation, and AO North America for this project. One of the authors certifies that he (TFH), or a member of his immediate family, has signed an agreement with DePuy Synthes (Warsaw, IN, USA) for consulting activities not related to the current study, and has not received payments or benefits, during the study period. One or more of the authors (CAS, KT) are employed at Eli Lilly (Indianapolis, IN, USA). All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research1 editors and board members are on file with the publication and can be viewed on request. Clinical Orthopaedics and Related Research1 neither advocates nor endorses the use of any treatment, drug, or device. Readers are encouraged to always seek additional information, including FDAapproval status, of any drug or device prior to clinical use. Each author certifies that his or her institution approved or waived approval for the reporting of this investigation and that all inves...

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“…Increased IL-1β and TNF-α levels are considered important influence factors in OA and RA and many therapeutic target (Cawston et al, 2003;Fan et al, 2007). Previous studies have shown that IL-1β and TNF-α can up-regulate aggrecanase expressions in OA and RA (Fan et al, 2007;Arner et al, 1998), which would predominantly increase aggrecan degradation and lead to glycosaminoglycan loss from the cartilage. Similar to OA and RA, it has been confirmed that IL-1β and TNF-α levels are also increased in adult KBD patients' synovial fluid (Tong and Yang, 2000).…”

Section: Discussionmentioning

confidence: 99%

Promotion of the articular cartilage proteoglycan degradation by T-2 toxin and selenium protective effect

Liu

Cao

Shi

et al. 2008

J. Zhejiang Univ. Sci. B

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Abstract:Objective: To identify the relationship between T-2 toxin and Kashin-Beck disease (KBD), the effects of T-2 toxin on aggrecan metabolism in human chondrocytes and cartilage were investigated in vitro. Methods: Chondrocytes were isolated from human articular cartilage and cultured in vitro. Hyaluronic acid (HA), soluble CD44 (sCD44), IL-1β and TNF-α levels in supernatants were measured by enzyme-linked immunosorbent assay (ELISA). CD44 content in chondrocyte membrane was determined by flow cytometry (FCM). CD44, hyaluronic acid synthetase-2 (HAS-2) and aggrecanases mRNA levels in chondrocytes were determined using reverse transcription polymerase chain reaction (RT-PCR). Immunocytochemical method was used to investigate expressions of BC-13, 3-B-3(−) and 2-B-6 epitopes in the cartilage reconstructed in vitro. Results: T-2 toxin inhibited CD44, HAS-2, and aggrecan mRNA expressions, but promoted aggrecanase-2 mRNA expression. Meanwhile, CD44 expression was found to be the lowest in the chondrocytes cultured with T-2 toxin and the highest in control plus selenium group. In addition, ELISA results indicated that there were higher sCD44, IL-1β and TNF-α levels in T-2 toxin group. Similarly, higher HA levels were also observed in T-2 toxin group using radioimmunoprecipitation assay (RIPA). Furthermore, using monoclonal antibodies BC-13, 3-B-3 and 2-B-6, strong positive immunostaining was found in the reconstructed cartilage cultured with T-2 toxin, whereas no positive staining or very weak staining was observed in the cartilage cultured without T-2 toxin. Selenium could partly inhibit the effects of T-2 toxin above. Conclusion: T-2 toxin could inhibit aggrecan synthesis, promote aggrecanases and pro-inflammatory cytokines production, and consequently induce aggrecan degradation in chondrocytes. These will perturb metabolism balance between aggrecan synthesis and degradation in cartilage, inducing aggrecan loss in the end, which may be the initiation of the cartilage degradation.

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Activation of Interleukin-1 Signaling Cascades in Normal and Osteoarthritic Articular Cartilage

Cited by 122 publications

References 42 publications

Rho/ROCK and MEK/ERK activation by transforming growth factor-α induces articular cartilage degradation

Rho/ROCK and MEK/ERK activation by transforming growth factor-α induces articular cartilage degradation

Intraarticular Matrix Metalloproteinases and Aggrecan Degradation Are Elevated After Articular Fracture

Promotion of the articular cartilage proteoglycan degradation by T-2 toxin and selenium protective effect

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