Pleiotropic roles of metallothioneins as regulators of chondrocyte apoptosis and catabolic and anabolic pathways during osteoarthritis pathogenesis

Abstract

ObjectiveThe zinc-ZIP8-MTF1 axis induces metallothionein (MT) expression and is a catabolic regulator of experimental osteoarthritis (OA) in mice. The main aim of the current study was to explore the roles and underlying molecular mechanisms of MTs in OA pathogenesis.MethodsExperimental OA in mice was induced by destabilisation of the medial meniscus or intra-articular injection of adenovirus carrying a target gene (Ad-Zip8, Ad-Mtf1, Ad-Epas1, Ad-Nampt, Ad-Mt1 or Ad-Mt2) into wild type, Zip8fl/fl; Col2a1-Cre, Mtf1fl/fl; Col2a1-Cre and Mt1/Mt2 double knockout mice. Primary cultured mouse chondrocytes were infected with Ad-Mt1 or Ad-Mt2, and gene expression profiles analysed via microarray and reverse transcription-PCR. Proteins in human and mouse OA cartilage were identified via immunostaining. Chondrocyte apoptosis in OA cartilage was determined using terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick end labelling (TUNEL).ResultsMTs were highly expressed in human and mouse OA cartilage. Hypoxia-inducible factor 2α, nicotinamide phosphoribosyltransferase and several proinflammatory cytokine pathways, as well as the zinc-ZIP8-MTF1 axis were identified as upstream regulators of MT expression. Genetic deletion of Mt1 and Mt2 enhanced cartilage destruction through increasing chondrocyte apoptosis. Unexpectedly, aberrant overexpression of MT2, but not MT1, induced upregulation of matrix-degrading enzymes and downregulation of matrix molecules through nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1) activation, ultimately leading to OA.ConclusionsMTs play an antiapoptotic role in post-traumatic OA. However, aberrant and chronic upregulation of MT2 triggers an imbalance between chondrocyte anabolism and catabolism, consequently accelerating OA development. Our findings collectively highlight pleiotropic roles of MTs as regulators of chondrocyte apoptosis as well as catabolic and anabolic pathways during OA pathogenesis.

Regulatory effects of zinc on cadmium-induced cytotoxicity in chronic inflammation

“…Moreover, MT-2s are overexpressed in the injured cartilage in OA, inducing chondrocyte apoptosis and matrix degradation through the metalloproteases (MMPs) MMP-3 and 13 [29]. MMP-3 has an important role in the invasive phenotype of RA synoviocytes [30–32].…”

Oxidative stress and thiols depletion impair tibia fracture healing in young men with type 2 diabetes

“…It agrees with serious oxidative damage, low level of bone markers namely calcium and ALP which were signifi-cantly decreased: Cas-3 = -0.014 + 0.0011×ROS* -0.056×Ca + 0.00005×ALP, F 3,20 = 28.32, P < 0.0001. It has been asserted that MTs play an antiapoptotic role in the post-traumatic process owing to strong antioxidant properties and anti-inflammatory potentials [15]. Our results revealed that MTs response to trauma depended on person's initial health status.…”

“…Metallothioneins (MTs) are stress-responsive, cysteine-rich, metal-binding, intra-and extracellular (including serum) proteins that are induced by and adapts to numerous stressful conditions [14,15]. Besides the transition metal detoxification and radical scavenging, MTs were also found to play an important role in immune response, cell proliferation and differentiation, and angiogenesis [14,15]. MTs would build a thiol pool up in cell cytosol which is able to diminish the damaging effect of GSH depletion.…”

Metallothionein 1 family profiling identifies MT1X as a tumor suppressor involved in the progression and metastastatic capacity of hepatocellular carcinoma

“…MT1s are involved in diverse functions, such as metal homeostasis, metal donation to different enzymes, angiogenesis, apoptosis, cell differentiation, radiation cell damage as well as carcinogenesis . Given their broad regulatory properties, MT1s have also been suggested to play important roles in cell senescence and various pathological processes, such as neurodegeneration, osteoarthritis, metabolic disorders, and certain immune processes . In recent years, some postulated pathophysiological effects of MT1s have been associated with distinct functional polymorphisms of MT1 genes …”