Local cytokine profiles in knee osteoarthritis: elevated synovial fluid interleukin-15 differentiates early from end-stage disease

Scanzello, Carla R.; Umoh, E.; Peßler, Frank; Díaz-Torné, Cèsar; Miles, T.; DiCarlo, Edward F.; Potter, Hollis G.; Mandl, Lisa A.; Marx, Robert G.; Rodeo, Scott A.; Goldring, Steven R.; Crow, Mary K.

doi:10.1016/j.joca.2009.02.011

Cited by 210 publications

(205 citation statements)

References 48 publications

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“…[79][80][81] In contrast, the two cytokines for which we observed differences between the OAC-AM and NC-AM group -namely IL-6 and IL-8 -have been demonstrated to increase in late versus early shoulder OA. 82 Combined, these points of comparison of NC-AM to OAC-AM to human disease suggest that our OAC-AM system may be serving as a disease mimic for later stage OA than the NC-AM system.…”

Section: Discussioncontrasting

confidence: 65%

A Three-Dimensional Chondrocyte-Macrophage Coculture System to Probe Inflammation in Experimental Osteoarthritis

Samavedi

Díaz‐Rodríguez

Erndt-Marino

et al. 2017

Tissue Engineering Part A

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The goal of the present study was to develop a fully three-dimensional (3D) coculture system that would allow for systematic evaluation of the interplay between activated macrophages (AMs) and chondrocytes in osteoarthritic disease progression and treatment. Toward this end, our coculture system was first validated against existing in vitro osteoarthritis models, which have generally cultured healthy normal chondrocytes (NCs)-in two-dimensional (2D) or 3D-with proinflammatory AMs in 2D. In this work, NCs and AMs were both encapsulated within poly(ethylene glycol) diacrylate hydrogels to mimic the native 3D environments of both cell types within the osteoarthritic joint. As with previous studies, increases in matrix metalloproteinases (MMPs) and proinflammatory cytokines associated with the early stages of osteoarthritis were observed during NC-AM coculture, as were decreases in protein-level Aggrecan and collagen II. Thereafter, the coculture system was extended to osteoarthritic chondrocytes (OACs) and AMs to evaluate the potential effects of AMs on pre-existing osteoarthritic phenotypes. OACs in coculture with AMs expressed significantly higher levels of MMP-1, MMP-3, MMP-9, MMP-13, IL-1b, TNF-a, IL-6, IL-8, and IFN-g compared to OACs in mono-culture, indicating that proinflammatory macrophages may intensify the abnormal matrix degradation and cytokine secretion already associated with OACs. Likewise, AMs cocultured with OACs expressed significantly more IL-1b and VEGF-A compared to AM mono-culture controls, suggesting that OACs may intensify abnormal macrophage activation. Finally, OACs cultured in the presence of nonactivated macrophages produced lower levels of MMP-9 and proinflammatory cytokines IL-1b, TNF-a, and IFN-g compared to OACs in the OAC-AM system, results that are consistent with anti-inflammatory agents temporarily reducing certain OA symptoms. In summary, the 3D coculture system developed herein captures several key features of inflammatory OA and may prove useful in future screening of therapeutic agents and/or assessment of disease progression mechanisms.

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Section: Discussioncontrasting

confidence: 65%

A Three-Dimensional Chondrocyte-Macrophage Coculture System to Probe Inflammation in Experimental Osteoarthritis

Samavedi

Díaz‐Rodríguez

Erndt-Marino

et al. 2017

Tissue Engineering Part A

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“…This eventually leads impaired ECM synthesis, cartilage degradation and, ultimately, development of OA [36,37].…”

Section: Page 6 Of 39mentioning

confidence: 99%

Melanocortin peptides protect chondrocytes from mechanically induced cartilage injury

Kaneva

Kerrigan

Grieco

et al. 2014

Biochemical Pharmacology

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Conclusion:Melanocortin peptide pre-treatment prevented chondrocyte death following mechanical impact to cartilage and led to a marked reduction of pro-inflammatory cytokines, whilst prompting the production of anti-inflammatory/pro-resolving cytokine IL-10.Development of small molecule agonists towards melanocortin receptors could thus be a viable approach for preventing chondrocyte inflammation and death within cartilage and represent an alternative approach for the treatment of osteoarthritis.

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“…A variety of animal OA models with ACL transection have shown upregulation of genes coding for aggrecanases and MMPs as well as increased concentrations of these destructive proteases [1,10,20,47]. Most human studies demonstrate elevated MMPs and aggrecan degradation in patients with OA as compared with healthy control subjects and that these proteases are more elevated in patients with end-stage OA compared with early OA [4,21,23,28,34]. In an effort to look specifically at the presence of proteolytic enzymes after traumatic injury, several authors have shown elevated MMPs and aggrecan degradation after ACL tear.…”

Section: Introductionmentioning

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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Local cytokine profiles in knee osteoarthritis: elevated synovial fluid interleukin-15 differentiates early from end-stage disease

Abstract: IL-15 is elevated in early knee OA, suggesting activation of an innate immune response in the SM. The association of IL-15 expression with CD8 transcripts and MMPs implicates this cytokine in OA pathogenesis and as a candidate therapeutic target.

Cited by 210 publications

References 48 publications

A Three-Dimensional Chondrocyte-Macrophage Coculture System to Probe Inflammation in Experimental Osteoarthritis

A Three-Dimensional Chondrocyte-Macrophage Coculture System to Probe Inflammation in Experimental Osteoarthritis

Melanocortin peptides protect chondrocytes from mechanically induced cartilage injury

Intraarticular Matrix Metalloproteinases and Aggrecan Degradation Are Elevated After Articular Fracture

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