Cartilage injury remains a major challenge in orthopedic surgery due to the fact that articular cartilage has only a limited capacity for intrinsic healing. Cartilage impaction is followed by a post-traumatic inflammatory response. Chondrocytes and synoviocytes are activated to produce inflammatory mediators and degradative enzymes which can induce a progradient cartilage self-destruction finally leading to secondary osteoarthritis (OA). However, an anti-inflammatory compensatory response is also detectable in cartilage by up-regulation of anti-inflammatory cytokines, probably a temporary attempt by chondrocytes to restore cartilage homeostasis. Matrix-assisted autologous chondrocyte transplantation (MACT) is a suitable technique for improving the rate of repair of larger articular cartilage defects. For MACT, autologous chondrocytes were isolated from a cartilage biopsy of a non-load bearing joint area. This technique requires sufficient expansion of differentiated autologous chondrocytes, which were then seeded on suitable biodegradable three-dimensional (3D) matrices to preform an extracellular cartilage matrix (ECM) before implantation into the defect. Cell expansion is accompanied by chondrocyte dedifferentiation, whereby substantial changes occur at multiple levels of chondrocyte synthetic profiles: including the ECM, cell surface receptors and cytoskeletal proteins. Since these dedifferentiated chondrocytes produce a non-specific mechanically inferior ECM, they are not suitable for MACT. 3D cultures are means of inducing and maintaining chondrocyte (re)differentiation and to preform ECM. The combination of MACT with anabolic growth factors and anti-inflammatory strategies using anti-inflammatory mediators might be useful for stabilizing the differentiated chondrocyte phenotype, to support neocartilage formation and inhibit post-traumatic cartilage inflammation and hence, the development of secondary OA.

Activation and dedifferentiation of chondrocytes: implications in cartilage injury and repair.

The impact of the local inflammatory response on the process of wound healing has been debated for decades. In particular, the question whether infiltrating macrophages and granulocytes promote or impede tissue repair has received much attention. In the present study, we show that wound healing is accelerated in mice deficient for the anti-inflammatory cytokine interleukin (IL)-10. IL-10−/− mice closed excisional wounds significantly earlier compared with IL-10-competent control littermates. This effect was attributable to accelerated epithelialization as well as enhanced contraction of the wound tissue in the mutant animals. Increased α-smooth muscle actin expression in IL-10-deficient mice suggests that augmented myofibroblast differentiation is responsible for the enhanced contraction of wounds in mutant mice. The number of macrophages infiltrating the wound tissue was significantly increased in IL-10−/− mice compared with control littermates suggesting that this cell type mediates the accelerated tissue repair. These results show for the first time that IL-10 can impede wound repair.

/pdf/accelerated-wound-closure-in-mice-deficient-for-interleukin-3hvdibr8qp.pdf

Accelerated wound closure in mice deficient for interleukin-10.

Methods of treating autoimmune diseases, allergic responses, cancer, or inflammatory diseases in an animal, promoting would healing, repairing epithelial damage and promoting angiogenesis in an organ or tissue of an animal by administering to the animal mesenchymal stem cells in an effective amount.

Mesenchymal stem cells and uses therefor

Owing to limited self-healing capacity, tendon ruptures and healing remain major orthopedic challenges. Increasing evidence suggests that post-traumatic inflammatory responses, and hence, cytokines are involved in both cases, and also in tendon exercise and homeostasis. This review summarizes interrelations known between the cytokines interleukin (IL)-1β, tumor necrosis factor (TNF)α, IL-6 and vascular endothelial growth factor (VEGF) in tendon to assess their role in tendon damage and healing. Exogenic cytokine sources are blood-derived leukocytes that immigrate in damaged tendon. Endogenous expression of IL-1β, TNFα, IL-6, IL-10 and VEGF was demonstrated in tendon-derived cells. As tendon is a highly mechanosensitive tissue, cytokine homeostasis and cell survival underlie an intimate balance between adequate biomechanical stimuli and disturbance through load deprivation and overload. Multiple interrelations between cytokines and tendon extracellular matrix (ECM) synthesis, catabolic mediators e.g. matrix-degrading enzymes, inflammatory and angiogenic factors (COX-2, PGE2, VEGF, NO) and cytoskeleton assembly are evident. Pro-inflammatory cytokines affect ECM homeostasis, accelerate remodeling, amplify biomechanical adaptiveness and promote tenocyte apoptosis. This multifaceted interplay might both contribute to and interfere with healing. Much work must be undertaken to understand the particular interrelation of these inflammatory and regulatory mediators in ruptured tendon and healing, which has relevance for the development of novel immunoregulatory therapeutic strategies.

The role of pro-inflammatory and immunoregulatory cytokines in tendon healing and rupture: new insights.

Osteoarthritis (OA) is a complex heterogeneous articular disease with multiple joint tissue involvement of varying severity and no regulatory-agency-approved disease-modifying drugs (DMOADs). In this review, we discuss the reasons necessitating the development of DMOADs for OA management, the classifications of clinical phenotypes or molecular/mechanistic endotypes from the viewpoint of targeted drug discovery, and then summarize the efficacy and safety profile of a range of targeted drugs in Phase 2 and 3 clinical trials directed to cartilage-driven, bone-driven, and inflammation-driven endotypes. Finally, we briefly put forward the reasons for failures in OA clinical trials and possible steps to overcome these barriers.

/pdf/the-development-of-disease-modifying-therapies-for-2xi6a1fgwn.pdf

The Development of Disease-Modifying Therapies for Osteoarthritis (DMOADs): The Evidence to Date

When we previously examined the participation of local expression of interleukin-10 (IL-10) and tumor necrosis factor-alpha (TNFalpha) in wound healing of an intestinal anastomosis under septic conditions in mice, we found that IL-10 and TNFalpha expressions were markedly enhanced around the anastomosis and that wound healing was impaired in this animal model. The purpose of the present study was to investigate the combined effect of IL-10 on proliferation and remodeling of the extracellular matrix (ECM) of cultured human skin fibroblasts. Human skin fibroblasts were cultured for 48 h with IL-10 and/or TNFalpha at various concentrations, then the proliferation rates were determined using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. The concentration of transforming growth factor-beta1 (TGFbeta1) in cell culture supernatants was measured by enzyme-linked immunosorbent assay, and type I collagen protein and matrix metalloproteinase-I (MMP-I) were detected by indirect immunofluorescence in cultured cells incubated for 48 h with 10 ng/ml of IL-10 and/or 10 ng/ml of TNFalpha. IL-10 itself had no effect on fibroblast proliferation, but reduced TNFalpha-induced fibroblast proliferation. The concentration of TGFbeta1 in cell culture supernatants was significantly lower in the presence of TNFalpha and IL-10 than in the presence of TNFalpha alone. Immunolabeling of fibroblasts for type I collagen protein was decreased in cells incubated with IL-10 and/or TNFalpha compared to controls. MMP-I immunolabeling was increased in cells incubated with IL-10, IL-10 and TNFalpha compared to control and cells incubated with TNFalpha. It is suggested that IL-10 is an inhibitory factor for the remodeling of the ECM during wound healing.

Interleukin-10 Suppresses Proliferation and Remodeling of Extracellular Matrix of Cultured Human Skin Fibroblasts

Aim. Survival and prognostic factors were analysed in patients who had undergone surgical resection with curative intention with the aim of identifying groups of patient with stage III and IV gallbladder cancer on the TNM classification who might benefit from surgery. Methods. Thirty-seven patients with advanced gallbladder cancer were studied, the cumulative survival rate for each group was calculated for each pTNM factor. Results. The 5-year survival rates in the stage III patients were 83.3%, while those for the stage IVA patients were 46.2%, and those for the stage IVB patients 16.7%. Conclusions. In patients with invasion of adjacent organs, including the liver and gastrointestinal tract, and rated as pT3 or pT4, extended surgery excising the invaded tissue may be justified. In patients with pN2 lymph-node metastasis, even without adjacent organ invasion, radical surgery may not achieve a good outcome.

Analysis of prognostic factors after surgery for stage III and IV gallbladder cancer

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Interleukin-10 Suppresses Proliferation and Remodeling of Extracellular Matrix of Cultured Human Skin Fibroblasts

Analysis of prognostic factors after surgery for stage III and IV gallbladder cancer