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

To investigate the impact of systemic inhibition of interleukin 6 (IL-6) or signal transducer and activator of transcription (Stat3) in an experimental model of osteoarthritis (OA). Expression of major catabolic and anabolic factors of cartilage was determined in IL-6-treated mouse chondrocytes and cartilage explants. The anti-IL-6-receptor neutralising antibody MR16-1 was used in the destabilisation of the medial meniscus (DMM) mouse model of OA. Stat3 blockade was investigated by the small molecule Stattic ex vivo and in the DMM model. In chondrocytes and cartilage explants, IL-6 treatment reduced proteoglycan content with increased production of matrix metalloproteinase (MMP-3 and MMP-13) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-4 and ADAMTS-5). IL-6 induced Stat3 and extracellular signal-regulated kinase (ERK) 1/2 signalling but not p38, c-Jun N-terminal kinase or Akt. In the DMM model, Stat3 was activated in cartilage, but neither in the synovium nor in the subchondral bone. Systemic blockade of IL-6 by MR16-1 alleviated DMM-induced OA cartilage lesions, impaired the osteophyte formation and the extent of synovitis. In the same model, Stattic had similar beneficial effects on cartilage and osteophyte formation. Stattic, but not an ERK1/2 inhibitor, significantly counteracted the catabolic effects of IL-6 on cartilage explants and suppressed the IL-6-induced chondrocytes apoptosis. 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.

Latourte A ，Cherifi C ，Maillet J ，Ea HK ，Bouaziz W ，Funck-Brentano T ，Cohen-Solal M ，Hay E ，Richette P ... -  《-》

Lithium protects against cartilage degradation in osteoarthritis.

To determine the actions of lithium chloride (LiCl) on catabolic events in human articular chondrocytes, and the effects of LiCl on the progression and severity of cartilage degradation in interleukin-1β (IL-1β)-treated mouse knee joints and after surgical induction of osteoarthritis (OA) in a mouse model. Human articular chondrocytes were treated with LiCl followed by IL-1β, and the expression levels of catabolic genes were determined by real-time polymerase chain reaction. To understand the mechanism by which LiCl affects catabolic events in articular chondrocytes after IL-1β treatment, the activation of NF-κB was determined using luciferase reporter assays, and the activities of MAPKs and the STAT-3 signaling pathway were determined by immunoblot analysis of total cell lysates. Cultures of mouse femoral head explants treated with IL-1β and a mouse model of surgically induced OA were used to determine the effects of LiCl on proteoglycan loss and cartilage degradation. LiCl treatment resulted in decreased catabolic marker messenger RNA levels and activation of NF-κB, p38 MAPK, and STAT-3 signaling in IL-1β-treated articular chondrocytes. Furthermore, LiCl directly inhibited IL-6-stimulated activation of STAT-3 signaling. Consequently, the loss of proteoglycan and severity of cartilage destruction in LiCl-treated mouse knee joints 8 weeks after OA induction surgery or in LiCl-treated mouse femoral head explants after IL-1β treatment were markedly reduced compared to that in vehicle-treated joints or explants. LiCl reduced catabolic events in IL-1β-treated human articular chondrocytes and attenuated the severity of cartilage destruction in IL-1β-treated mouse femoral head explants and in the knee joints of mice with surgically induced OA, acting via inhibition of the activities of the NF-κB, p38, and STAT-3 signaling pathways.

Minashima T ，Zhang Y ，Lee Y ，Kirsch T ... -  《-》

Ghrelin prevents articular cartilage matrix destruction in human chondrocytes.

Osteoarthritis (OA) is the most common form of arthritis worldwide. Excessive production of pro-inflammatory cytokines such as interleukin-1β (IL-1β) plays a key role in the pathogenesis of OA. OA is generally characterized by degradation of extracellular matrixes such as type II collagen and aggrecans mediated by matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS). Ghrelin is a secreted peptide hormone regulating appetite and the distribution and rate of use of energy. However, the physiological and pharmacological roles of Ghrelin on the pathological progression of OA haven't been reported before. In the current study, our results indicate that Ghrelin reduced IL-1β-induced expression of MMP-3, MMP-13, ADAMTS-4 and ADAMTS-5 in a concentration-dependent manner. Notably, Ghrelin ameliorated IL-1β-induced degradation of type II collagen and aggrecan. Mechanistically, Ghrelin is able to inhibit the expression of IRF-1 mediated by inactivating the JAK2/STAT3 pathway. However, Ghrelin didn't have any impact on IL-1β induced activation of p38. Taken together, our findings identify a novel function of Ghrelin on inhibiting the degradation of type II collagen and aggrecan.

Liu J ，Cao L ，Gao X ，Chen Z ，Guo S ，He Z ，Qian Y ，Yu Y ，Wang G ... -  《-》

Role of interleukin 6 (IL-6)/IL-6R-induced signal tranducers and activators of transcription and mitogen-activated protein kinase/extracellular.

Legendre F ，Bogdanowicz P ，Boumediene K ，Pujol JP ... -  《JOURNAL OF RHEUMATOLOGY》

Aggravation of ADAMTS and matrix metalloproteinase production and role of ERK1/2 pathway in the interaction of osteoarthritic subchondral bone osteoblasts and articular cartilage chondrocytes -- possible pathogenic role in osteoarthritis.

Prasadam I ，Crawford R ，Xiao Y 《-》