Endocannabinoid Research Group, Institute of Biomolecular Chemistry (ICB), National Research Council of Italy, 80078 Pozzuoli, Italy.
Institute of Genetics and Biophysics Adriano Buzzati-Traverso, National Research Council of Italy, 80131 Naples, Italy.
Cells. 2021 May 14;10(5):1199. doi: 10.3390/cells10051199.
Bone is a highly complex and metabolically active tissue undergoing a continuous remodeling process, which endures throughout life. A complex cell-signaling system that plays role in regulating different physiological processes, including bone remodeling, is the endocannabinoid system (ECS). Bone mass expresses CB1 and CB2 cannabinoid receptors and enzymatic machinery responsible for the metabolism of their endogenous ligands, endocannabinoids (AEA and 2-AG). Exogenous AEA is reported to increase the early phase of human osteoblast differentiation in vitro. However, regarding this cell context little is known about how endocannabinoids and endocannabinoid-related -acylethanolamines like PEA and OEA are modulated, in vitro, during cell differentiation and, in vivo, over time up to adulthood. Here we characterized the endocannabinoid tone during the different phases of the osteoblast differentiation process in MC3T3-E1 cells, and we measured endocannabinoid levels in mouse femurs at life cycle stages characterized by highly active bone growth (i.e., of juvenile, young adult, and mature adult bone). Endocannabinoid tone was significantly altered during osteoblast differentiation, with substantial OEA increment, decline in 2-AG and AEA, and consistent modulation of their metabolic enzymes in maturing and mineralized MC3T3-E1 cells. Similarly, in femurs, we found substantial, age-related, decline in 2-AG, OEA, and PEA. These findings can expand existing knowledge underlying physiological bone cell function and contribute to therapeutic strategies for preventing bone-related metabolic changes accruing through lifespan.
骨骼是一种高度复杂且代谢活跃的组织，不断进行重塑过程，这一过程贯穿人的一生。内源性大麻素系统（ECS）是一种复杂的细胞信号系统，在调节包括骨骼重塑在内的不同生理过程中发挥作用。骨组织表达 CB1 和 CB2 大麻素受体以及负责代谢其内源性配体（内源性大麻素）的酶机制。有报道称，外源性 AEA 可增加体外人成骨细胞分化的早期阶段。然而，关于这种细胞环境，我们知之甚少，即内源性大麻素和内源性大麻素相关的酰基乙醇胺（如 PEA 和 OEA）在细胞分化过程中以及在体内随时间变化至成年期间是如何被调节的。在这里，我们在 MC3T3-E1 细胞的成骨细胞分化过程的不同阶段表征了内源性大麻素的张力，并测量了在生命周期中具有高度活跃骨生长阶段（即幼年、年轻成年和成熟成年骨）的小鼠股骨中的内源性大麻素水平。在成骨细胞分化过程中，内源性大麻素张力发生显著变化，OEA 显著增加，2-AG 和 AEA 减少，并且在成熟和矿化的 MC3T3-E1 细胞中其代谢酶的调节保持一致。同样，在股骨中，我们发现 2-AG、OEA 和 PEA 随年龄显著下降。这些发现可以扩展生理骨细胞功能的现有知识，并有助于预防与寿命相关的代谢变化的治疗策略。
