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Clinical-like cryotherapy improves footprint patterns and reduces synovial inflammation in a rat model of post-traumatic knee osteoarthritis.

ABSTRACT: Cryotherapy is a non-pharmacological treatment commonly used to control inflammation and improve function after acute traumas. However, there are no definitive findings about its effects on chronic joint diseases such as knee osteoarthritis (KOA). The aim of this study was to investigate the effects of clinical-like cryotherapy on functional impairment and synovial inflammation in a rat model of KOA generated by anterior cruciate ligament transection (ACLT). Thirty-two male Wistar rats were randomly divided into four groups (n?=?8/group): Control, KOA, KOA?+?Cryotherapy and KOA?+?Placebo. The last two groups were submitted to the relevant interventions twice a day for five days (61 to 65), with each session lasting 20?min. Gait test, skin temperature, thermal response threshold and joint swelling were assessed in all groups before ACLT surgery, and pre (60^th day) and post (66^th day) intervention protocols. On day 66, the animals were euthanized and exsanguinated to remove the synovial membrane for histopathological examination and synovial fluid to determine the leukocyte count and cytokine concentration. After the intervention period (66^th day), footprint area only increased in the KOA?+?Cryotherapy group (P?=?0.004; 14%) when compared to KOA and KOA?+?Placebo, but did not differ from controls. Cryotherapy lowered the synovial fluid leukocyte count (P?

SUBMITTER: Barbosa GM

PROVIDER: S-EPMC6787208 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Clinical-like cryotherapy improves footprint patterns and reduces synovial inflammation in a rat model of post-traumatic knee osteoarthritis.

Barbosa Germanna Medeiros GM Cunha Jonathan Emanuel JE Cunha Thiago Mattar TM Martinho Lizandra Botaro LB Castro Paula Aiello Tomé Souza PATS Oliveira Francisco Fábio Bezerra FFB Cunha Fernando Queiróz FQ Ramalho Fernando Silva FS Salvini Tania Fátima TF

Scientific reports 20191010 1

Cryotherapy is a non-pharmacological treatment commonly used to control inflammation and improve function after acute traumas. However, there are no definitive findings about its effects on chronic joint diseases such as knee osteoarthritis (KOA). The aim of this study was to investigate the effects of clinical-like cryotherapy on functional impairment and synovial inflammation in a rat model of KOA generated by anterior cruciate ligament transection (ACLT). Thirty-two male Wistar rats were rand ...[more]

PMID: 31601862

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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: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.

Dataset Information

Clinical-like cryotherapy improves footprint patterns and reduces synovial inflammation in a rat model of post-traumatic knee osteoarthritis.

Publications

Clinical-like cryotherapy improves footprint patterns and reduces synovial inflammation in a rat model of post-traumatic knee osteoarthritis.

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