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Macrophage proliferation distinguishes 2 subgroups of knee osteoarthritis patients.

ABSTRACT: Osteoarthritis (OA) is a leading cause of disability, globally. Despite an emerging role for synovial inflammation in OA pathogenesis, attempts to target inflammation therapeutically have had limited success. A better understanding of the cellular and molecular processes occurring in the OA synovium is needed to develop novel therapeutics. We investigated macrophage phenotype and gene expression in synovial tissue of OA and inflammatory-arthritis (IA) patients. Compared with IA, OA synovial tissue contained higher but variable proportions of macrophages (P < 0.001). These macrophages exhibited an activated phenotype, expressing folate receptor-2 and CD86, and displayed high phagocytic capacity. RNA sequencing of synovial macrophages revealed 2 OA subgroups. Inflammatory-like OA (iOA) macrophages are closely aligned to IA macrophages and are characterized by a cell proliferation signature. In contrast, classical OA (cOA) macrophages display cartilage remodeling features. Supporting these findings, when compared with cOA, iOA synovial tissue contained higher proportions of macrophages (P < 0.01), expressing higher levels of the proliferation marker Ki67 (P < 0.01). These data provide new insight into the heterogeneity of OA synovial tissue and suggest distinct roles of macrophages in pathogenesis. Our findings could lead to the stratification of OA patients for suitable disease-modifying treatments and the identification of novel therapeutic targets.

SUBMITTER: Wood MJ

PROVIDER: S-EPMC6413777 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Macrophage proliferation distinguishes 2 subgroups of knee osteoarthritis patients.

Wood Matthew J MJ Leckenby Adam A Reynolds Gary G Spiering Rachel R Pratt Arthur G AG Rankin Kenneth S KS Isaacs John D JD Haniffa Muzlifah A MA Milling Simon S Hilkens Catharien Mu CM

JCI insight 20190124 2

Osteoarthritis (OA) is a leading cause of disability, globally. Despite an emerging role for synovial inflammation in OA pathogenesis, attempts to target inflammation therapeutically have had limited success. A better understanding of the cellular and molecular processes occurring in the OA synovium is needed to develop novel therapeutics. We investigated macrophage phenotype and gene expression in synovial tissue of OA and inflammatory-arthritis (IA) patients. Compared with IA, OA synovial tiss ...[more]

PMID: 30674730

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Project description:BackgroundWe recently developed a model of stratified exercise therapy, consisting of (i) a stratification algorithm allocating patients with knee osteoarthritis (OA) into one of the three subgroups ('high muscle strength subgroup' representing a post-traumatic phenotype, 'low muscle strength subgroup' representing an age-induced phenotype, and 'obesity subgroup' representing a metabolic phenotype) and (ii) subgroup-specific exercise therapy. In the present study, we aimed to test the construct validity of this algorithm.MethodsData from five studies (four exercise therapy trial cohorts and one cross-sectional cohort) were used to test the construct validity of our algorithm by 63 a priori formulated hypotheses regarding three research questions: (i) are the proportions of patients in each subgroup similar across cohorts? (15 hypotheses); (ii) are the characteristics of each of the subgroups in line with their proposed underlying phenotypes? (30 hypotheses); (iii) are the effects of usual exercise therapy in the 3 subgroups in line with the proposed effect sizes? (18 hypotheses).ResultsBaseline data from a total of 1211 patients with knee OA were analyzed for the first and second research question, and follow-up data from 584 patients who were part of an exercise therapy arm within a trial for the third research question. In total, the vast majority (73%) of the hypotheses were confirmed. Regarding our first research question, we found similar proportions in each of the three subgroups across cohorts, especially for three cohorts. Regarding our second research question, subgroup characteristics were almost completely in line with the proposed underlying phenotypes. Regarding our third research question, usual exercise therapy resulted in similar, medium to large effect sizes for knee pain and physical function for all three subgroups.ConclusionWe found mixed results regarding the construct validity of our stratification algorithm. On the one hand, it is a valid instrument to consistently allocate patients into subgroups that aligned our hypotheses. On the other hand, in contrast to our hypotheses, subgroups did not differ substantially in effects of usual exercise therapy. An ongoing trial will assess whether this algorithm accompanied by subgroup-specific exercise therapy improves clinical and economic outcomes.

Project description:BackgroundPain from osteoarthritis (OA) is one of the top causes of disability worldwide, but effective treatment is lacking. Nociceptive factors are released by activated synovial macrophages in OA, but depletion of synovial macrophages paradoxically worsens inflammation and tissue damage in previous studies. Rather than depleting macrophages, we hypothesized that inhibiting macrophage activation may improve pain without increasing tissue damage. We aimed to identify key mechanisms mediating synovial macrophage activation and test the role of STAT signaling in macrophages on pain outcomes in experimental knee OA.MethodsWe induced experimental knee OA in rats via knee destabilization surgery, and performed RNA sequencing analysis on sorted synovial tissue macrophages to identify macrophage activation mechanisms. Liposomes laden with STAT1 or STAT6 inhibitors, vehicle (control), or clodronate (depletion control) were delivered selectively to synovial macrophages via serial intra-articular injections up to 12 weeks after OA induction. Treatment effects on knee and hindpaw mechanical pain sensitivity were measured during OA development, along with synovitis, cartilage damage, and synovial macrophage infiltration using histopathology and immunofluorescence. Lastly, crosstalk between drug-treated synovial tissue and articular chondrocytes was assessed in co-culture.ResultsThe majority of pathways identified by transcriptomic analyses in OA synovial macrophages involve STAT signaling. As expected, macrophage depletion reduced pain, but increased synovial tissue fibrosis and vascularization. In contrast, STAT6 inhibition in macrophages led to marked, sustained improvements in mechanical pain sensitivity and synovial inflammation without worsening synovial or cartilage pathology. During co-culture, STAT6 inhibitor-treated synovial tissue had minimal effects on healthy chondrocyte gene expression, whereas STAT1 inhibitor-treated synovium induced changes in numerous cartilage turnover-related genes.ConclusionThese results suggest that STAT signaling is a major mediator of synovial macrophage activation in experimental knee OA. STAT6 may be a key mechanism mediating the release of nociceptive factors from macrophages and the development of mechanical pain sensitivity. Whereas therapeutic depletion of macrophages paradoxically increases inflammation and fibrosis, blocking STAT6-mediated synovial macrophage activation may be a novel strategy for OA-pain management without accelerating tissue damage.

Project description:Arthrofibrosis is characterized by excessive extracellular matrix (ECM) deposition that results in restricted joint motion after total knee arthroplasty (TKA). Current surgical and pharmacologic treatment options are limited. Therefore, an in vitro model for joint myofibroblastogenesis is valuable to investigate the arthrofibrotic process and identify diagnostic biomarkers and treatment options. In this study, we obtained intraoperative posterior capsule (PC), quadriceps tendon (QT), and suprapatellar pouch (SP) tissue from knees of four patients undergoing primary TKA for osteoarthritis and characterized primary outgrowth cells from these tissues in the absence and presence of transforming growth factor beta 1 (TGFβ1), a pro-myofibroblastic cytokine. Light microscopy of knee outgrowth cells revealed spindle-shaped cells while immunofluorescence (IF) established staining for the fibroblast-specific antigen TE-7 and Vimentin, which are characteristics of fibroblasts. These fibroblasts differentiate readily into myofibroblasts as highlighted by enhanced alpha smooth muscle actin (ACTA2) mRNA and protein expression and increased collagen mRNA (i.e., collagen type 1 (COL1A1) and collagen type 3 (COL3A1)) expression and collagenous matrix deposition in the presence of TGFβ1. Of note, these studies also revealed that knee-derived fibroblasts are more sensitive to TGFβ1-mediated myofibroblastogenesis than adipose-derived mesenchymal stem cells. Importantly, while outgrowth fibroblasts isolated from four patients and three anatomical regions exhibit similar gene expression profiles, these knee fibroblasts form a unique gene expression cluster within the fibroblast niche as revealed by RNA-sequencing analysis. In conclusion, our study provides a fibroblast/myofibroblast model of outgrowth knee cells derived from patients undergoing primary TKA that can be employed to assess myofibroblast-related processes and test novel pharmacological strategies in vitro for arthrofibrosis.

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Macrophage proliferation distinguishes 2 subgroups of knee osteoarthritis patients.

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Macrophage proliferation distinguishes 2 subgroups of knee osteoarthritis patients.

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