University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Center of Excellence in Morphological and Surgical Studies (CEMyQ), Faculty of Medicine, Universidad de la Frontera, Temuco 4811230, Chile.
Int J Mol Sci. 2024 Jun 1;25(11):6104. doi: 10.3390/ijms25116104.
Bone regeneration remains a significant clinical challenge, often necessitating surgical approaches when healing bone defects and fracture nonunions. Within this context, the modulation of adenosine signaling pathways has emerged as a promising therapeutic option, encouraging osteoblast activation and tempering osteoclast differentiation. A literature review of the PubMed database with relevant keywords was conducted. The search criteria involved in vitro or in vivo models, with clear methodological descriptions. Only studies that included the use of indirect adenosine agonists, looking at the effects of bone regeneration, were considered relevant according to the eligibility criteria. A total of 29 articles were identified which met the inclusion and exclusion criteria, and they were reviewed to highlight the preclinical translation of adenosine agonists. While preclinical studies demonstrate the therapeutic potential of adenosine signaling in bone regeneration, its clinical application remains unrealized, underscoring the need for further clinical trials. To date, only large, preclinical animal models using indirect adenosine agonists have been successful in stimulating bone regeneration. The adenosine receptors (A, A, A, and A) stimulate various pathways, inducing different cellular responses. Specifically, indirect adenosine agonists act to increase the extracellular concentration of adenosine, subsequently agonizing the respective adenosine receptors. The agonism of each receptor is dependent on its expression on the cell surface, the extracellular concentration of adenosine, and its affinity for adenosine. This comprehensive review analyzed the multitude of indirect agonists currently being studied preclinically for bone regeneration, discussing the mechanisms of each agonist, their cellular responses in vitro, and their effects on bone formation in vivo.
骨再生仍然是一个重大的临床挑战，当治疗骨缺损和骨折不愈合时，通常需要手术方法。在这种情况下，调节腺苷信号通路已成为一种有前途的治疗选择，可促进成骨细胞的激活并抑制破骨细胞的分化。通过使用相关关键字对 PubMed 数据库进行了文献综述。搜索标准涉及体外或体内模型，并具有明确的方法学描述。仅根据资格标准，将那些包含间接腺苷激动剂使用的研究纳入相关研究，这些研究研究了骨再生的影响。共有 29 篇文章符合纳入和排除标准，并对其进行了回顾，以突出腺苷激动剂的临床前转化。虽然临床前研究表明腺苷信号在骨再生中的治疗潜力，但尚未实现其临床应用，这突显了进一步临床试验的必要性。迄今为止，只有使用间接腺苷激动剂的大型临床前动物模型成功地刺激了骨再生。腺苷受体（A1、A2A、A2B 和 A3）刺激各种途径，诱导不同的细胞反应。具体而言，间接腺苷激动剂作用于增加细胞外腺苷浓度，随后激动相应的腺苷受体。每个受体的激动取决于其在细胞表面的表达、细胞外腺苷浓度及其对腺苷的亲和力。这篇全面的综述分析了目前正在进行的用于骨再生的多种间接激动剂，讨论了每种激动剂的机制、它们在体外的细胞反应以及它们对体内骨形成的影响。
