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Synovial perlecan is required for osteophyte formation in knee osteoarthritis.

ABSTRACT: The osteophyte associated with osteoarthritis (OA) is a bony outgrowth formed at the margins of the affected joint through endochondral ossification-like processes. However, the mechanism of osteophyte formation and its pathogenesis are unclear. Perlecan (Hspg2), a heparan sulfate proteoglycan, is expressed in many extracellular tissues and plays critical roles in skeletal development and diseases. The aim of the present study is to identify the role of synovial perlecan in osteophyte formation using perinatal lethality rescued perlecan-knockout mice (Hspg2(-/-)-Tg) wherein perlecan expression is lacking in the synovial and other tissues, except for cartilage. We analyzed the development of osteophytes in joints of Hspg2(-/-)-Tg mice in two different animal models: the surgical OA model, in which the medial collateral ligament was transected and the medial meniscus was resected, and the TGF-?-induced osteophyte formation model. In the surgical OA model, the osteophyte size and maturation were significantly reduced in the OA joints of Hspg2(-/-)-Tg mice compared with control mice, while OA developed on the medial side of the knee joints with no differences in the cartilage degradation score or synovitis score between control and Hspg2(-/-)-Tg mice. The reduced osteophyte formation in Hspg2(-/-)-Tg mice was associated with reduced cell proliferation and chondrogenesis. In the TGF-? model, the osteophyte size and maturation were also significantly reduced in Hspg2(-/-)-Tg mice compared with control mice. Our findings suggest that synovial perlecan plays an important role in osteophyte development in OA, and they provide insights that may facilitate the development of OA therapy.

SUBMITTER: Kaneko H

PROVIDER: S-EPMC3843243 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Synovial perlecan is required for osteophyte formation in knee osteoarthritis.

Kaneko Haruka H Ishijima Muneaki M Futami Ippei I Tomikawa-Ichikawa Naoki N Kosaki Keisuke K Sadatsuki Ryo R Yamada Yoshihiko Y Kurosawa Hisashi H Kaneko Kazuo K Arikawa-Hirasawa Eri E

Matrix biology : journal of the International Society for Matrix Biology 20130120 3-4

The osteophyte associated with osteoarthritis (OA) is a bony outgrowth formed at the margins of the affected joint through endochondral ossification-like processes. However, the mechanism of osteophyte formation and its pathogenesis are unclear. Perlecan (Hspg2), a heparan sulfate proteoglycan, is expressed in many extracellular tissues and plays critical roles in skeletal development and diseases. The aim of the present study is to identify the role of synovial perlecan in osteophyte formation ...[more]

PMID: 23339896

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Project description:ObjectiveSynovial membrane inflammation is common in osteoarthritis (OA) and increases cartilage injury. However, synovial fluid and histology studies suggest that OA inflammatory responses are not homogeneous. Greater understanding of these responses may provide new insights into OA disease mechanisms. We undertook this study to develop a novel multiparameter approach to phenotype synovial responses in knee OA.MethodsCell composition and soluble protein production were measured by flow cytometry and multiplex enzyme-linked immunosorbent assay in synovium collected from OA patients undergoing knee replacement surgery (n = 35).ResultsTesting disaggregation conditions showed that aggressive digestion improved synovial cell yield and mesenchymal staining by flow cytometry, but it negatively impacted CD4+ T cell and CD56+ natural killer cell staining. Less aggressive digestion preserved these markers and showed highly variable T cell infiltration (range 0-43%; n = 32). Correlation analysis identified mesenchymal subpopulations associated with different nonmesenchymal populations, including macrophages and T cells (CD45+CD11b+HLA-DR+ myeloid cells with PDPN+CD73+CD90-CD34- mesenchymal cells [r = 0.65, P < 0.0001]; and CD45+CD3+ T cells with PDPN+CD73+CD90+CD34+ mesenchymal cells [r = 0.50, P = 0.003]). Interleukin-6 (IL-6) measured by flow cytometry strongly correlated with IL-6 released by ex vivo culture of synovial tissue (r = 0.59, P = 0.0012) and was highest in mesenchymal cells coexpressing CD90 and CD34. IL-6, IL-8, complement factor D, and IL-10 release correlated positively with tissue cellularity (P = 0.0042, P = 0.018, P = 0.0012, and P = 0.038, respectively). Additionally, increased CD8+ T cell numbers correlated with retinol binding protein 4 (P = 0.033). Finally, combining flow cytometry and multiplex data identified patient clusters with different types of inflammatory responses.ConclusionWe used a novel approach to analyze OA synovium, identifying patient-specific inflammatory clusters. Our findings indicate that phenotyping synovial inflammation may provide new insights into OA patient heterogeneity and biomarker development.

Project description:BackgroundSynovitis occurring frequently in osteoarthritis (OA) may be a targeted outcome. There are no data examining whether synovitis changes following intra-articular intervention.MethodsPersons aged 40 years and older with painful knee OA participated in an open label trial of intra-articular steroid therapy. At all time points they completed the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire. They had a contrast-enhanced (CE) MRI immediately prior to an intra-articular steroid injection with a repeat scan within 20 days. Response status was assessed using the Osteoarthritis Research Society International (OARSI) response criteria. OARSI responders were followed until their pain relapsed either within 20% of baseline or 6 months, shortly after which a third MRI was performed. Synovial tissue volume (STV) was measured on postcontrast knee images. We looked at changes in the STV and in pain, and their association.Results120 subjects with preinjection and postinjection CE MRI were followed. Their mean age was 62.3 years (SD=10.3) and 62 (52%) were women. The median time between injection and follow-up scan was 8 days (IQR 7-14 days). 85/120 (71%) were OARSI responders. Pain decreased (mean change in KOOS=+23.9; 95% CI 20.1 to 27.8, p<0.001) following steroid injection, as did mean STV (mean change=-1071 mm(3); 95% CI -1839 mm(3) to -303 mm(3), p=0.01). Of the 80 who returned for a third MRI, pain relapsed in 57, and in the 48 of those with MRI data, STV increased between follow-up and final visit (+1220 mm(3); 95% CI 25 mm(3) to 2414 mm(3), p=0.05). 23 were persistent responders at 6 months and, in these, STV did not increase (mean change=-202 mm(3); 95% CI -2008 mm(3) to 1604 mm(3), p=0.83). Controlling for variation over time, there was a significant association between synovitis volume and KOOS pain (b coefficient-change in KOOS pain score per 1000 mm(3) change in STV=-1.13; 95% CI -1.87 to -0.39, p=0.003), although STV accounted for only a small proportion of the variance in change in pain.ConclusionsSynovial tissue volume in knee OA shrinks following steroid therapy, and rebounds in those whose pain relapses. It can be considered a treatment target in symptomatic knee OA.Trial registration numberISRCTN07329370.

Dataset Information

Synovial perlecan is required for osteophyte formation in knee osteoarthritis.

Publications

Synovial perlecan is required for osteophyte formation in knee osteoarthritis.

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