Systemic inhibition of IL-6/Stat3 signalling protects against experimental osteoarthritis

Latourte, Augustin; Cherifi, Chahrazad; Maillet, Jérémy; Ea, Hang‐Korng; Bouaziz, Wafa; Funck‐Brentano, Thomas; Cohen‐Solal, Martine; Haÿ, Eric; Richette, Pascal

doi:10.1136/annrheumdis-2016-209757

Cited by 278 publications

(211 citation statements)

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“…Based on previous published papers by us (Nasi et al, 2016a,b) and by others (Ryu et al, 2011; Latourte et al, 2016), we suggest that IL-6-targeted strategies could lead to new therapeutic options for OA, by interrupting the vicious circle between BCP crystal formation and IL-6 production by chondrocytes (see Figure 5). …”

Section: Discussionmentioning

confidence: 54%

“…The conflicting results about the role of IL-1, but also other cytokines such as IL-6 (de Hooge et al, 2005; Ryu et al, 2011; Latourte et al, 2016; Nasi et al, 2016a) in experimental models of OA, could reflect species difference, differences in age and sex of the animals used, variability in the method of OA induction (different progression of joint degeneration, degrees of inflammation, degrees of unpaired loading for each experimental OA model).”…”

Section: Discussionmentioning

confidence: 99%

“…However, IL-1 was not significantly overexpressed in moderate OA compared to mild OA (McNulty et al, 2013). In experimental murine OA, IL-6 neutralization, its genetic deficiency or inhibition of its signaling molecule Stat3 with a non-peptidic small molecule prevented cartilage damage (Ryu et al, 2011; Latourte et al, 2016). In addition, in menisectomized mice, increasing deposits of BCP-crystals were observed around the joint and correlated with cartilage degradation and IL-6 expression (Nasi et al, 2016a).…”

Section: Introductionmentioning

confidence: 99%

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Revisiting the Role of Interleukin-1 Pathway in Osteoarthritis: Interleukin-1α and -1β, and NLRP3 Inflammasome Are Not Involved in the Pathological Features of the Murine Menisectomy Model of Osteoarthritis

Nasi

et al. 2017

Front. Pharmacol.

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Background: Innate immune response components such as toll-like receptors (TLRs) and NLRP3-inflammasome act in concert to increase IL-1α/β secretion by synovial macrophages. Previous results suggest that IL-1α/β could be an important mediator involved in the pathogenesis of osteoarthritis (OA).Objectives: The aim of our study was to evaluate the role of NLRP3, IL-1β, and IL-1α in the menisectomy (MNX) model of murine OA.Methods: Murine chondrocytes (CHs) and bone marrow-derived machrophages (BMDM) were stimulated with hydroxyapatite (HA) crystals, a form of calcium-containing crystal found in human OA, and IL-1β and IL-6 secretion assayed by ELISA.Conversely, the ability of IL-1β and IL-6 to induce CHs calcification was assessed in vitro by Alizarin red staining. Knees from 8 to 10 weeks old C57Bl/6J wild-type (WT) (n = 7), NLRP3−/− (n = 9), IL-1α−/− (n = 5), and IL-1β−/− (n = 5) mice were menisectomized, using the sham-operated contralateral knee as control. 8 weeks later, knee cartilage degradation and synovial inflammation were evaluated by histology. In addition, apoptotic chondrocytes, metalloproteases activity, and collagen-type 2 expression were evaluated in all mice. Joint calcification and subchondral bone parameters were quantified by CT-scan in WT and IL-1β−/− menisectomized knees.Results: In vitro, HA crystals induced significant increased IL-6 secretion by CHs, while IL-1β remained undetectable.Conversely, both IL-6 and IL-1β were able to increase chondrocytes mineralization. In vivo, operated knees exhibited OA features compared to sham-operated knees as evidenced by increased cartilage degradation and synovial inflammation. In menisectomized KO mice, severity and extent of cartilage lesions were similar (IL-1α−/− mice) or exacerbated (IL-1β−/− and NLRP3−/− mice) compared to that of menisectomized WT mice. Metalloproteases activity, collagen-type 2 expression, chondrocytes apoptosis, and synovial inflammation were similar between KO and WT mice menisectomized knees. Moreover, the extent of joint calcification in osteoarthritic knees was comparable between IL-1β−/− and WT mice.Conclusions: MNX knees recapitulated features of OA, i.e, cartilage destruction, synovial inflammation, cell death, and joint calcification. Deficiency of IL-1α did not impact on the severity of these features, whereas deficiency of IL-1β or of NLRP3 led to increased cartilage erosion. Our results suggest that IL-1α and IL-1β are not key mediators in this murine OA model and may explain the inefficiency of IL-1 targeted therapies in OA.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Revisiting the Role of Interleukin-1 Pathway in Osteoarthritis: Interleukin-1α and -1β, and NLRP3 Inflammasome Are Not Involved in the Pathological Features of the Murine Menisectomy Model of Osteoarthritis

Nasi

et al. 2017

Front. Pharmacol.

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“…This could potentially be regulated in part by the STAT3 target gene Myc , which both promotes proliferation and inhibits hypertrophy in developing chondrocytes 22. In contrast, inhibition of STAT3 downstream of exogenous IL-6 is chondroprotective, reducing the severity of OA-like pathology in a mouse model 17. These data implicate IL-6 family cytokine signalling as a major regulator of articular chondrocyte biology with potentially context-specific effects.…”

Section: Introductionmentioning

confidence: 84%

Drug-induced modulation of gp130 signalling prevents articular cartilage degeneration and promotes repair

et al. 2018

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“…The biological actions of miR-29a to synovial tissue metabolism in the development of asymptomatic OA is worthy of investigation. Moreover, synovitis occurs in the development of collagenase- 46 , destabilized medial meniscus- 47 and mechanical stress-induced 26 OA knees in mice. miR-29a deficiency modulates inflammatory reactions in mice with collagen-induced arthritic joints 48 .…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-29a Counteracts Synovitis in Knee Osteoarthritis Pathogenesis by Targeting VEGF

Lee

Lian

et al. 2017

Sci Rep

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Synovitis contributes to the development of osteoarthritis (OA) of the knee. MicroRNAs regulate joint microenvironment homeostasis and deterioration. This study was undertaken to characterize the actions of microRNA-29a (miR-29a) to synovial remodeling in OA joints. Synovial specimens isolated from patients with end-stage OA knees showed abundant fibrotic matrix and vessel histopathology concomitant with weak miR-29a expression. In vitro, miR-29a knockdown caused synovial fibroblasts to exhibit high expressions of collagen III, TGF-β1, MMP9, MMP13, and ADAMTS5, whereas miR-29a overexpression diminished these joint-deleterious factors. In collagenase-mediated OA pathogenesis, miR-29a-overexpressing transgenic mice showed minor responses to hyperplasia, macrophage infiltration, fibrosis, hyperangiogenesis, and VEGF expression in synovial lesions. These effects mitigated articular cartilage loss and gait aberrance of injured joints. Intra-articular administration of miR-29a precursor lessened the collagenase aggravation of excessive synovial remodeling reactions and thereby sustained joint tissue integrity. miR-29a lowered VEGF production and angiogenic activities in synovial fibroblasts through targeting the 3′-UTR of VEGF. Taken together, miR-29a deficiency exacerbated synovitis pathogenesis in the end-stage OA knees. miR-29a signaling fends off excessive synovial angiogenesis and fibrosis, which delays joint destruction. This study sheds new light on the protective effects against synovial deterioration and the therapeutic advantage of miR-29a in OA knees.

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Systemic inhibition of IL-6/Stat3 signalling protects against experimental osteoarthritis

Abstract: IL-6 induces chondrocyte catabolism mainly via Stat3 signalling, a pathway activated in cartilage from joint subjected to DMM. Systemic blockade of IL-6 or STAT-3 can alleviate DMM-induced OA in mice.

Cited by 278 publications

References 47 publications

Revisiting the Role of Interleukin-1 Pathway in Osteoarthritis: Interleukin-1α and -1β, and NLRP3 Inflammasome Are Not Involved in the Pathological Features of the Murine Menisectomy Model of Osteoarthritis

Revisiting the Role of Interleukin-1 Pathway in Osteoarthritis: Interleukin-1α and -1β, and NLRP3 Inflammasome Are Not Involved in the Pathological Features of the Murine Menisectomy Model of Osteoarthritis

Drug-induced modulation of gp130 signalling prevents articular cartilage degeneration and promotes repair

MicroRNA-29a Counteracts Synovitis in Knee Osteoarthritis Pathogenesis by Targeting VEGF

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