Seal Anouska, Hughes Megan, Wei Fei, Pugazhendhi Abinaya S, Ngo Christopher, Ruiz Jonathan, Schwartzman Jonathan D, Coathup Melanie J
Biionix Cluster, University of Central Florida, Orlando, FL 32827, USA.
School of Biosciences, Cardiff University, Cardiff CF10 3AT, UK.
Int J Mol Sci. 2024 Mar 5;25(5):3024. doi: 10.3390/ijms25053024.
The human skeleton is a metabolically active system that is constantly regenerating via the tightly regulated and highly coordinated processes of bone resorption and formation. Emerging evidence reveals fascinating new insights into the role of sphingolipids, including sphingomyelin, sphingosine, ceramide, and sphingosine-1-phosphate, in bone homeostasis. Sphingolipids are a major class of highly bioactive lipids able to activate distinct protein targets including, lipases, phosphatases, and kinases, thereby conferring distinct cellular functions beyond energy metabolism. Lipids are known to contribute to the progression of chronic inflammation, and notably, an increase in bone marrow adiposity parallel to elevated bone loss is observed in most pathological bone conditions, including aging, rheumatoid arthritis, osteoarthritis, and osteomyelitis. Of the numerous classes of lipids that form, sphingolipids are considered among the most deleterious. This review highlights the important primary role of sphingolipids in bone homeostasis and how dysregulation of these bioactive metabolites appears central to many chronic bone-related diseases. Further, their contribution to the invasion, virulence, and colonization of both viral and bacterial host cell infections is also discussed. Many unmet clinical needs remain, and data to date suggest the future use of sphingolipid-targeted therapy to regulate bone dysfunction due to a variety of diseases or infection are highly promising. However, deciphering the biochemical and molecular mechanisms of this diverse and extremely complex sphingolipidome, both in terms of bone health and disease, is considered the next frontier in the field.
人体骨骼是一个代谢活跃的系统，通过骨吸收和形成这两个严格调控且高度协调的过程不断再生。新出现的证据揭示了鞘脂类物质，包括鞘磷脂、鞘氨醇、神经酰胺和1-磷酸鞘氨醇，在骨骼稳态中的作用，令人着迷。鞘脂类是一类主要的高生物活性脂质，能够激活包括脂肪酶、磷酸酶和激酶在内的不同蛋白质靶点，从而赋予除能量代谢之外的独特细胞功能。已知脂质会促进慢性炎症的发展，值得注意的是，在大多数病理性骨病中，包括衰老、类风湿性关节炎、骨关节炎和骨髓炎，都观察到骨髓脂肪增多与骨质流失增加同时出现。在众多形成的脂质类别中，鞘脂类被认为是最具危害性的。本综述强调了鞘脂类在骨骼稳态中的重要首要作用，以及这些生物活性代谢物的失调如何似乎是许多慢性骨相关疾病的核心。此外，还讨论了它们对病毒和细菌宿主细胞感染的侵袭、毒力和定植的作用。许多临床需求仍未得到满足，迄今为止的数据表明，未来使用针对鞘脂类的疗法来调节因各种疾病或感染引起的骨功能障碍极有前景。然而，从骨骼健康和疾病的角度解读这个多样且极其复杂的鞘脂组的生化和分子机制，被认为是该领域未来的前沿方向。
