Holliday L Shannon, Patel Shivani S, Rody Wellington J
Department of Orthodontics, University of Florida College of Dentistry, Gainesville, FL 32610, USA.
Department of Anatomy & Cell Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Extracell Vesicles Circ Nucl Acids. 2021;2(1):18-28. doi: 10.20517/evcna.2020.02. Epub 2021 Mar 30.
Receptor activator of nuclear factor kappa B-ligand (RANKL), its receptor RANK, and osteoprotegerin which binds RANKL and acts as a soluble decoy receptor, are essential controllers of bone remodeling. They also play important roles in establishing immune tolerance and in the development of the lymphatic system and mammary glands. In bone, RANKL stimulates osteoclast formation by binding RANK on osteoclast precursors and osteoclasts. This is required for bone resorption. Recently, RANKL and RANK have been shown to be functional components of extracellular vesicles (EVs). Data linking RANKL and RANK in EVs to biological regulatory roles are reviewed, and crucial unanswered questions are examined. RANKL and RANK are transmembrane proteins and their presence in EVs allows them to act at a distance from their cell of origin. Because RANKL-bearing osteocytes and osteoblasts are often spatially distant from RANK-containing osteoclasts in vivo, this may be crucial for the stimulation of osteoclast formation and bone resorption. RANK in EVs from osteoclasts has the capacity to stimulate a RANKL reverse signaling pathway in osteoblasts that promotes bone formation. This serves to couple bone resorption with bone formation and has inspired novel bifunctional therapeutic agents. RANKL- and RANK- containing EVs in serum may serve as biomarkers for bone and immune pathologies. In summary, EVs containing RANKL and RANK have been identified as intercellular regulators in bone biology. They add complexity to the central signaling network responsible for maintaining bone. RANKL- and RANK-containing EVs are attractive as drug targets and as biomarkers.
核因子κB受体活化因子配体（RANKL）、其受体RANK以及结合RANKL并作为可溶性诱饵受体发挥作用的骨保护素，是骨重塑的关键调控因子。它们在建立免疫耐受以及淋巴系统和乳腺的发育过程中也发挥着重要作用。在骨骼中，RANKL通过与破骨细胞前体和破骨细胞上的RANK结合来刺激破骨细胞形成。这是骨吸收所必需的。最近，RANKL和RANK已被证明是细胞外囊泡（EVs）的功能成分。本文综述了EVs中RANKL和RANK与生物学调节作用相关的数据，并探讨了关键的未解决问题。RANKL和RANK是跨膜蛋白，它们在EVs中的存在使它们能够在远离其起源细胞的位置发挥作用。由于在体内，携带RANKL的骨细胞和成骨细胞通常与含RANK的破骨细胞在空间上相距较远，这对于刺激破骨细胞形成和骨吸收可能至关重要。破骨细胞来源的EVs中的RANK能够刺激成骨细胞中的RANKL反向信号通路，从而促进骨形成。这有助于将骨吸收与骨形成联系起来，并催生了新型双功能治疗药物。血清中含RANKL和RANK的EVs可能作为骨骼和免疫疾病的生物标志物。总之，含有RANKL和RANK的EVs已被确定为骨生物学中的细胞间调节因子。它们增加了负责维持骨骼的核心信号网络的复杂性。含RANKL和RANK的EVs作为药物靶点和生物标志物具有吸引力。
