Lithium Protects Against Cartilage Degradation in Osteoarthritis

Abstract

Objective. 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-1␤ (IL-1␤)-treated mouse knee joints and after surgical induction of osteoarthritis (OA) in a mouse model.Methods. Human articular chondrocytes were treated with LiCl followed by IL-1␤, 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-1␤ treatment, the activation of NF-B 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-1␤ and a mouse model of surgically induced OA were used to determine the effects of LiCl on proteoglycan loss and cartilage degradation.Results. LiCl treatment resulted in decreased catabolic marker messenger RNA levels and activation of NF-B, p38 MAPK, and STAT-3 signaling in IL-1␤-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-1␤ treatment were markedly reduced compared to that in vehicle-treated joints or explants. Conclusion.LiCl reduced catabolic events in IL-1␤-treated human articular chondrocytes and attenuated the severity of cartilage destruction in IL-1␤-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-B, p38, and STAT-3 signaling pathways.

Lithium chloride prevents interleukin‐1β induced cartilage degradation and loss of mechanical properties

“…Previous studies report that LiCl blocks inflammatory signaling and prevents matrix catabolism in cartilage explants . To confirm these results, we assessed the effects of LiCl treatment on the induction of PGE 2 and NO release in cartilage explants in response to IL‐1β.…”

“…In this study, Hui et al demonstrate that LiCl selectively inhibits the phosphorylation and activation of p38 MAPK in response to IL‐1β thus preventing the induction of MMP‐1 and MMP‐13 and the resulting cartilage degradation that follows. More recently, Minashima et al demonstrated that intra‐articular injection of LiCl into the joint cavity significantly reduces cartilage damage in mouse models following the surgical induction of OA . However, in other studies LiCl is shown to induce apoptosis and to disrupt the sulphation of glycosaminoglycans which is likely to impact on proteoglycan hydration and tissue mechanics.…”

Emerging targets in osteoarthritis therapy

“…Canonical Wnt signaling induced by Wnt3a or WISP1 promotes the switch of TGF-β signaling towards ALK1 and Smad 1/5/8 [•137] and mechanical load-mediated suppression of sclerostin requires TGF-β [147]. Although lithium chloride stimulates β-catenin signaling via inhibition of GSK-3, it inhibits catabolic events in surgically induced OA in mice via NF-κB, p38, and Stat3 signaling [148]. …”

Lithium-silicate sol–gel bioactive glass and the effect of lithium precursor on structure–property relationships

“…However, recent investigations have demonstrated that lithium can be used in other fields of medicine, especially for the regeneration of damaged bone and osteochondral tissue [2][3][4][5][6][7]. Arioka et al showed that lithium chloride inhibits GSK-3, one of the main regulators of the Wnt/b-catenin pathway, which plays a crucial role in the differentiation of osteoblasts.…”