T-2 toxin inhibits osteoblastic differentiation and mineralization involving mutual regulation between Wnt signaling pathway and autophagy

Mycotoxins are toxic metabolites produced by different kinds of fungi and widely exist in soil, water source and various agro-environmental matrices [1]. T-2 toxin, a trichothecene mycotoxin produced by Fusarium species, is the most frequently-detected mycotoxin contaminant in cereals, livestock feed and other agricultural products worldwide. According to a global survey, the prevalence of T-2 toxin is regional and Europe having the highest contamination rate [2]. A study in the Czech Republic showed that the detection rate of T-2 toxin in spring barley samples was 88% [3]. In Croatia, 70% oats tested positive for sum T-2/HT-2 toxin [4]. According to a 6-year survey of mycotoxins in animal feed in Poland, T-2 toxin was detected in 98.9% and 96.4% of complete feeds and total mixed ration respectively, with the highest content of up to 131 μg/kg [5]. T-2 toxin can be enriched in food chains due to the stable physicochemical property, eventually harm human health and agricultural development [6]. T-2 toxin could easily be absorbed by the intestine and mainly accumulates in skeletal system. T-2 toxin causes bone dysplasia and degenerative joint changes [7,8] and is an environmental risk factor of many bone diseases represented by Kaschin-Beck disease. Nevertheless, the osteotoxic mechanism of T-2 toxin is not fully understood.

Skeletal growth and development depend upon the formation of growth plate cartilage by chondrocytes and the bone-forming function of osteoblast. A study has shown that 0.32, 1.6 and 8 ng/ml T-2 toxin caused cartilage matrix degradation through TGF-β1/Smad3 pathway [9]. 10, 20, 40 ng/ml T-2 toxin induced hypertrophic chondrocytes oxidative stress and inflammation through ROS–NF–κB–HIF–2α pathway [10]. The IC50 of T-2 toxin on hypertrophic chondrocytes was 20 ng/ml [10]. The IC50 of T-2 toxin on another chondrocytes (C28/I2) was 36.84 ng/ml and 8 ng/ml T-2 toxin caused chondrocyte oxidative stress and apoptosis [11]. Therefore, the toxicity mechanisms of T-2 toxin on chondrocyte have been extensively studied. As another important bone forming cell during bone development, osteoblast undergo differentiation and mineralization to eventually form bone. During differentiation, osteoblast secrete large amounts of alkaline phosphatase (ALP) and differentiate into osteocyte and bone lining cell [12]. Mineralization is the formation of hydroxyapatite in extracellular matrix secreted by mature osteoblast. Abnormal differentiation and mineralization of osteoblast results in bone formation disorders which have been implicated in the nosogenesis of many bone disease, including bone dysplasia, fragility fracture, and osteomalacia [13]. However, the effects of T-2 toxin on osteoblast have still not yet been investigated so far.

The Wnt signaling pathway is mainly divided into two categories, namely the classic Wnt signaling pathway (Wnt/β-catenin signaling pathway) and the non-canonical Wnt signaling pathway. The classic Wnt signaling pathway (hereafter referred to as “Wnt signaling pathway”) is a critical pathway in regulating bone formation. Wnt signaling pathway regulates osteoblastic differentiation and mineralization by bone formation factors osterix (OSX), runt-related transcription factor-2 (RUNX-2), collagen types I (Col-I) and osteocalcin (OCN). Our previous research indicated that T-2 toxin induced femur formation disorders with down-regulated Wnt signaling pathway in mice [14]. More importantly, T-2 toxin repressed Wnt signaling pathway in chondrocyte in vitro. Additionally, up-regulated Wnt signaling pathway alleviates intestinal injury and reproductive dysfunction caused by trichothecene mycotoxin [15,16]. Autophagy is a protecting mechanism to against cellular stress, dynamic process of degradation of cellular macromolecules and organelles by lysosomal hydrolases [17]. During development and differentiation, the drastic cellular and tissue remodeling is often accompanied by autophagy [18]. Studies have shown that suppression of autophagy impairs bone formation with osteoblastic differentiation disorders in mice [19,20]. Autophagy is also closely associated with osteoblastic mineralization. Autophagic vesicles can serve as vehicles to secrete hydroxyapatite participating in osteoblastic mineralization [21]. Moreover, animal experiments showed that T-2 toxin promoted autophagy in mouse liver and femur [14,22]. Therefore, there is reason to believe that Wnt signaling pathway and autophagy are possible mechanisms and potential therapeutic targets of T-2 bone toxicity. The purpose of this investigation was to explore the effects of T-2 toxin on differentiation and mineralization of osteoblast and the regulatory mechanisms of Wnt signaling pathway and autophagy.

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