Targeted proteomics of hip articular cartilage in OA and fracture patients

Hosseininia, Shahrzad; Önnerfjord, Patrik; Dahlberg, Leif

doi:10.1002/jor.24158

Cited by 20 publications

(14 citation statements)

References 32 publications

(64 reference statements)

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“…In humans, chondrodysplasia-causing mutations in COMP, collagen IX, or MATN3 are frequently associated with premature osteoarthritis. Matrilin-3 is present at low levels in the joint articular surface and its deposition is upregulated in cartilage and in the synovial fluid of patients with OA as a consequence of cartilage degradation [56][57][58][59][60]. Studies with recombinant MATN3 and human primary chondrocytes have revealed that MATN3 exhibits a context-dependent anabolic or catabolic function by influencing the expression of pro-inflammatory cytokines, ECM degradation enzymes, and ECM synthesis [59,[61][62][63] through the modulation of protein kinase B (AKT) [59], interleukin-6 [62], and interleukin-1 [63,64] signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Mice Lacking the Matrilin Family of Extracellular Matrix Proteins Develop Mild Skeletal Abnormalities and Are Susceptible to Age-Associated Osteoarthritis

Fleischhauer

Nicolae

et al. 2020

IJMS

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Matrilins (MATN1, MATN2, MATN3 and MATN4) are adaptor proteins of the cartilage extracellular matrix (ECM), which bridge the collagen II and proteoglycan networks. In humans, dominant-negative mutations in MATN3 lead to various forms of mild chondrodysplasias. However, single or double matrilin knockout mice generated previously in our laboratory do not show an overt skeletal phenotype, suggesting compensation among the matrilin family members. The aim of our study was to establish a mouse line, which lacks all four matrilins and analyze the consequence of matrilin deficiency on endochondral bone formation and cartilage function. Matn1-4−/− mice were viable and fertile, and showed a lumbosacral transition phenotype characterized by the sacralization of the sixth lumbar vertebra. The development of the appendicular skeleton, the structure of the growth plate, chondrocyte differentiation, proliferation, and survival were normal in mutant mice. Biochemical analysis of knee cartilage demonstrated moderate alterations in the extractability of the binding partners of matrilins in Matn1-4−/− mice. Atomic force microscopy (AFM) revealed comparable compressive stiffness but higher collagen fiber diameters in the growth plate cartilage of quadruple mutant compared to wild-type mice. Importantly, Matn1-4−/− mice developed more severe spontaneous osteoarthritis at the age of 18 months, which was accompanied by changes in the biomechanical properties of the articular cartilage. Interestingly, Matn4−/− mice also developed age-associated osteoarthritis suggesting a crucial role of MATN4 in maintaining the stability of the articular cartilage. Collectively, our data provide evidence that matrilins are important to protect articular cartilage from deterioration and are involved in the specification of the vertebral column.

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Section: Discussionmentioning

confidence: 99%

Mice Lacking the Matrilin Family of Extracellular Matrix Proteins Develop Mild Skeletal Abnormalities and Are Susceptible to Age-Associated Osteoarthritis

Fleischhauer

Nicolae

et al. 2020

IJMS

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“…The presence of IL-17 in synovial fluid may also discriminate an OA subtype with faster cartilage loss, reduced osteophytes, and increased adipokines. Increased pain in hip OA patients is associated with increased IL-6, visfatin, and leptin, while in knee OA patients, increased leptin, reduced adiponectin and reduced adiponectin–leptin ratio are associated with pain [ 89 – 91 ]. Given the association of OA with metabolic disease, it is feasible that lipid and metabolomic markers may define specific OA subtypes and impact disease progression as they do in cancer [ 92 – 94 ].…”

Section: Disease Stratification—breaking Down a Spectrum Of Diseases mentioning

confidence: 99%

Chondroprotective Factors in Osteoarthritis: a Joint Affair

Mimpen

Snelling

2019

Curr Rheumatol Rep

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Purpose of the Review Osteoarthritis is widely regarded as a spectrum of conditions that affect all joint tissues, typified by a common entity: cartilage loss. Here, we review recent progress and challenges in chondroprotection and discuss new strategies to prevent cartilage loss in osteoarthritis. Recent Findings Advances in clinical, molecular, and cellular characterization are enabling improved stratification of osteoarthritis subtypes. Integration of next-generation sequencing and "omics" approaches with clinically relevant readouts shows promise in delineating both subtypes of disease and meaningful trial end points. Novel delivery strategies are enabling jointspecific delivery. Summary Chondroprotection requires a whole joint approach, stratification of patient groups, and use of patient-relevant end points. Drug development should continue to explore new targets, while using modern technologies and recent knowledge to revisit unsuccessful therapeutics from the past. The overarching goal for chondroprotection is to provide the right treatment(s) for the right patient at the right time.

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“…Kjelgaard-Petersen et al (2018) have previously shown that full-depth bovine articular cartilage explants (BEX) treated with oncostatin M in combination with TNFα (O + T) were a reliable translational model for rheumatoid arthritis by successfully back-translating the serological biomarker results from a phase III clinical study (OSKIRA-1) [32]. Proteomic technologies allow for a large-scale unbiased investigation, making it possible to identify factors involved in joint disease progression and build a library of mediators: previous studies have revealed numerous cytokines, proteases, and matrix fragments in serum, synovial fluid, and articular cartilage of OA patients [33][34][35][36]. Therefore, adapting the BEX model for studying IL-17-mediated articular cartilage changes and combining it with proteomics could contribute to a better understanding of molecular events involved in IL-17-mediated cartilage turnover and identification of its biomarkers.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the interleukin-17 effect on articular cartilage in a translational model: an explorative study

Sinkevičiūtė

Aspberg

et al. 2020

BMC Rheumatol

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Background: Osteoarthritis (OA) is a progressive, chronic disease characterized by articular cartilage destruction. The pro-inflammatory cytokine IL-17 levels have been reported elevated in serum and synovial fluid of OA patients and correlated with increased cartilage defects and bone remodeling. The aim of this study was to characterize an IL-17-mediated articular cartilage degradation ex-vivo model and to investigate IL-17 effect on cartilage extracellular matrix protein turnover. Methods: Full-depth bovine femoral condyle articular cartilage explants were cultured in serum-free medium for three weeks in the absence, or presence of cytokines: IL-17A (100 ng/ml or 25 ng/ml), or 10 ng OSM combined with 20 ng/ml TNFα (O + T). RNA isolation and PCR analysis were performed on tissue lysates to confirm IL-17 receptor expression. GAG and ECM-turnover biomarker release into conditioned media was assessed with dimethyl methylene blue and ELISA assays, respectively. Gelatin zymography was used for matrix metalloproteinase (MMP) 2 and MMP9 activity assessment in conditioned media, and shotgun LC-MS/MS for identification and label-free quantification of proteins and protein fragments in conditioned media. Western blotting was used to validate MS results. Results: IL-17RA mRNA was expressed in bovine full-depth articular cartilage and the treatment with IL-17A did not interfere with metabolic activity of the model. IL-17A induced cartilage breakdown; conditioned media GAG levels were 3.6-fold-elevated compared to untreated. IL-17A [100 ng/ml] induced ADAMTS-mediated aggrecan degradation fragment release (14-fold increase compared to untreated) and MMP-mediated type II collagen fragment release (6-fold-change compared to untreated). MS data analysis revealed 16 differentially expressed proteins in IL-17A conditioned media compared to untreated, and CHI3L1 upregulation in conditioned media in response to IL-17 was confirmed by Western blotting. Conclusions: We showed that IL-17A has cartilage modulating potential. It induces collagen and aggrecan degradation indicating an upregulation of MMPs. This was confirmed by zymography and mass spectrometry data. We also showed that the expression of other cytokines is induced by IL-17A, which provide further insight to the pathways that are active in response to IL-17A. This exploratory study confirms that IL-17A may play a role in cartilage pathology and that the applied model may be a good tool to further investigate it.

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Targeted proteomics of hip articular cartilage in OA and fracture patients

Cited by 20 publications

References 32 publications

Mice Lacking the Matrilin Family of Extracellular Matrix Proteins Develop Mild Skeletal Abnormalities and Are Susceptible to Age-Associated Osteoarthritis

Mice Lacking the Matrilin Family of Extracellular Matrix Proteins Develop Mild Skeletal Abnormalities and Are Susceptible to Age-Associated Osteoarthritis

Chondroprotective Factors in Osteoarthritis: a Joint Affair

Characterization of the interleukin-17 effect on articular cartilage in a translational model: an explorative study

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