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Abstract：
Unveiling of the mechanism involved in the occurrence and development of trauma-induced heterotopic ossification (tHO) is highly demanding due to current ineffective clinical treatment for it. Previous studies proposed that hydrogen sulfide (H2S) was vital for fate determination of stem cells, suggesting a potential role in the regulation of tHO development. In the current study, We found that expression of metabolic enzyme within sulfur conversion pathway was enhanced after tendon injury, leading to H2S accumulation within the tHO region. Increased production of endogenous H2S was shown to promote aberrant osteogenic activity of tendon-derived stem cells (TDSCs), which accelerated tHO formation. The inhibition of metabolic enzyme of H2S production or directly absorption of H2S could abolished osteogenic induction of TDSCs and the formation of tHO. Mechanistically, through RNA sequencing combined with rescue experiments, we demonstrated that activation of Ca2+/ERK pathway was the downstream molecular event of H2S-induced osteogenic commitment of TDSCs and tHO. For treatment strategy exploration, zine oxide nanoparticles (ZnO) as an effective H2S elimination material was validated to ideally halt the tHO formation in this study. Furthermore, in terms of chirality of nanoparticles, D-ZnO or L-ZnO nanoparticles showed superiority over R-ZnO nanoparticles in both clearing of H2S and inhibition of tHO. Our study not only revealed the mechanism of tHO through the endogenous gas signaling event from a new perspective, but also presented a applicable platform for elimination of the inordinate gas production, thus aiding the development of clinical treatment for tHO.
摘要：
由于目前对其临床治疗无效，因此揭示与创伤诱发的异位骨化（tHO）的发生和发展有关的机制要求很高。先前的研究表明，硫化氢（H2S）对于干细胞的命运决定至关重要，提示在调节tHO发育中的潜在作用。在目前的研究中,我们发现肌腱损伤后硫转化途径中代谢酶的表达增强，导致H2S在tHO区域内积聚。内源性H2S的产生增加被证明可以促进肌腱源性干细胞（TDSC）的异常成骨活性，加速了THO的形成。抑制H2S产生的代谢酶或直接吸收H2S可以消除TDSC的成骨诱导和tHO的形成。机械上,通过RNA测序结合拯救实验，我们证明Ca2+/ERK通路的激活是H2S诱导的TDSC和tHO成骨承诺的下游分子事件。对于治疗策略的探索，在这项研究中，氧化锌纳米颗粒（ZnO）作为有效的H2S消除材料被验证为理想地停止了tHO的形成。此外，就纳米粒子的手性而言，D-ZnO或L-ZnO纳米颗粒在清除H2S和抑制tHO方面均优于R-ZnO纳米颗粒。我们的研究不仅从一个新的角度揭示了tHO通过内源性气体信号事件的机制,还提出了一个消除天然气生产过度的适用平台，从而帮助发展tHO的临床治疗。
