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The Therapeutic Potential of Exogenous Adenosine Triphosphate (ATP) for Cartilage Tissue Engineering

机译：外源三磷酸腺苷（ATP）对软骨组织工程的治疗潜力

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Objective:While mechanical stimuli can be used to enhance the properties of engineered cartilage, a promising alternative may be to directly harness the underlying mechanotransduction pathways responsible. Our initial studies on the adenosine triphosphate (ATP)-purinergic receptor pathway demonstrated that stimulation by exogenous ATP improved tissue growth and properties but elicited matrix turnover under high doses (250 μM) potentially due to the accumulation of extracellular inorganic pyrophosphate (ePPi). Therefore, the purpose of this study was to identify the mechanism of ATP-mediated catabolism and determine a therapeutic dose to maximize the anabolic effect.Design:Isolated bovine articular chondrocytes were seeded in high-density, 3-dimensional culture supplemented with varying doses of ATP for 4 weeks. The effects on biosynthesis, matrix metalloproteinase 13 (MMP-13) protein activity, and PPi accumulation were determined. Separate monolayer experiments were conducted to determine the effect of ePPi on MMP-13 activity.Results:High doses of ATP resulted in an increase in ePPi accumulation (by 54%) and MMP-13 activity (by 39%). Monolayer experiments confirmed a link between increased ePPi accumulation and MMP-13 activity, which appeared to require calcium and was inhibited by the MEK1/2 inhibitor U0126. Cultures supplemented with 62.5 to 125 μM ATP favored an anabolic response, which represented the therapeutic dose range.Conclusions:A therapeutic dose range of exogenous ATP to improve the properties of engineered cartilage has been identified, and a possible catabolic mechanism involving excess PPi was determined. Future research into PPi signal transduction and pathological crystal formation is necessary to maximize the beneficial effect of exogenous ATP on chondrocyte cultures.
机译：目的：虽然机械刺激可用于增强工程软骨的特性，但有希望的替代方法可能是直接利用潜在的机械传导途径。我们对三磷酸腺苷（嘌呤）嘌呤能受体途径的初步研究表明，外源ATP刺激可改善组织生长和特性，但在高剂量（250μM）下引起基质更新，这可能是由于细胞外无机焦磷酸盐（ePPi）的积累。因此，本研究的目的是确定ATP介导的分解代谢的机制并确定最大的合成代谢作用的治疗剂量。设计：将分离的牛关节软骨细胞接种在高密度3维培养物中，并补充不同剂量的ATP 4周。确定了对生物合成，基质金属蛋白酶13（MMP-13）蛋白质活性和PPi积累的影响。结果：高剂量的ATP导致ePPi积累（增加54％）和MMP-13活性（增加39％），从而增加了ePPi对MMP-13活性的影响。单层实验证实，ePPi积累与MMP-13活性之间存在联系，MMP-13活性似乎需要钙，并被MEK1 / 2抑制剂U0126抑制。补充62.5至125μMATP的培养物促进了合成代谢反应，这代表了治疗剂量范围。结论：已确定了可改善工程软骨特性的外源ATP的治疗剂量范围，并确定了可能涉及过量PPi的分解代谢机制。为了使外源性ATP对软骨细胞培养的有益作用最大化，有必要对PPi信号转导和病理性晶体形成进行进一步的研究。

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