The Crosstalk between MYC and Metabolism during Osteoclastogenesis

类风湿性关节炎（RA）是一种慢性炎症性疾病， 产生促炎细胞因子，并驱动炎症状态，导致受影响的细胞的破坏。 接头.骨质侵蚀是RA的诊断标志，通常先于临床症状的发展。 症状破骨细胞是有效地吸收骨的髓系细胞，并且直接负责 骨侵蚀和发病率。因此，我们的总体假设是， 破骨细胞的分化和活性可能会产生新的治疗目标，限制病理性骨 再吸收我们已经发现转录因子MYC和MYC依赖性转录程序是 在破骨细胞分化早期由RANKL激活。尽管MYC被卷入了 破骨细胞生成，MYC影响体内平衡和功能的确切机制， 破骨细胞仍大量未被探索。我们发现MYC是破骨细胞分化所必需的， 在破骨细胞生成过程中调节与代谢和翻译相关的基因。 有趣的是，在滑膜破骨细胞前体中，MYC和NFATc1的表达均显著升高， （OCP），其具有更大的分化成破骨细胞的潜力。OCP是 他们被认为重新编程他们的新陈代谢，以满足破骨细胞的能量需求，破骨细胞必须融合成 多核细胞和合成分子来吸收骨。然而，代谢的贡献 破骨细胞分化的途径和调节代谢重编程的关键分子， 很好理解。因此，我们假设MYC在RANKL诱导的代谢中起重要作用， 重新编程和MYC是炎症性关节炎中产生过度活跃的破骨细胞的主要贡献者之一。 骨疾病通过改变特定的代谢途径。为了验证我们的假设，我们提出了三个具体的 目的：1）研究MYC在体内破骨细胞生成中的作用，2）确定其分子机制 MYC的调节和功能的基础，以及3）研究MYC调节的机制 破骨细胞的代谢重编程。这项研究将促进我们对MYC在以下方面的作用的理解： 破骨细胞分化，在破骨细胞分化过程中发生的代谢重编程的作用， 破骨细胞生成过程中MYC和代谢重编程之间的串扰。此外，作为治疗 直接靶向MYC激活的效应分子目前在临床上不可用， 在破骨细胞分化中起重要作用的MYC下游可能作为新的治疗药物 治疗和预防病理性骨吸收的靶点。因此，这一事件的总体影响 该项目的目的是产生见解，不仅将扩大我们对MYC在以下领域的作用的理解： 骨免疫学，但也可以利用开发治疗干预，以抑制骨吸收 由MYC表达失调导致的破骨细胞过度活跃。

Rheumatoid arthritis (RA) is a chronic inflammatory disease in which immune cells and synovial fibroblasts produce pro-inflammatory cytokines and drive an inflammatory state leading to the destruction of affected joints. Bone erosion is a diagnostic hallmark of RA and commonly precedes the development of clinical symptoms. Osteoclasts are myeloid lineage cells that effectively resorb bone and are directly responsible for bone erosion and morbidity in RA. Thus, our overall hypothesis is that a better understanding of the regulation of osteoclast differentiation and activity is likely to yield novel targets for therapies that limit pathological bone resorption. We have found that the transcription factor MYC and MYC-dependent transcriptional programs are activated by RANKL during early osteoclast differentiation. Although MYC has been implicated in osteoclastogenesis, the precise mechanisms by which MYC affects the homeostasis and function of osteoclasts remain largely unexplored. We have found that MYC is required for osteoclast differentiation and regulates the genes that are associated with metabolism and translation during osteoclastogenesis. Interestingly, both MYC and NFATc1 expression are significantly elevated in synovial osteoclast precursors (OCPs) from patients with RA that have a greater potential for differentiating into osteoclasts. OCPs are thought to reprogram their metabolism to meet the energy demands of osteoclasts, which must fuse into multinucleated cells and synthesize molecules to resorb bone. However, the contribution of metabolic pathways to osteoclast differentiation and the key molecule that regulates metabolic reprogramming are not well understood. Therefore, we hypothesize that MYC plays an important role in RANKL-induced metabolic reprogramming and MYC is one of the major contributors to generate hyperactive osteoclasts in inflammatory bone diseases by altering specific metabolic pathways. To test our hypothesis, we proposed three specific aims :1) to characterize the role of MYC in osteoclastogenesis in vivo, 2) to identify the molecular mechanisms underlying the regulation and function of MYC, and 3) to investigate mechanisms by which MYC regulates metabolic reprogramming in osteoclasts. This study will advance our understanding of the role of MYC in osteoclast differentiation, the role of metabolic reprogramming occurring during osteoclast differentiation, and the crosstalk between MYC and metabolic reprogramming during osteoclastogenesis. In addition, as therapies directly targeting MYC activation are not presently available in the clinic, identification of effector molecule(s) downstream of MYC that play important roles in osteoclast differentiation may serve as novel therapeutic targets for the treatment and prevention of pathological bone resorption. Therefore, the overall impact of this project is to yield insights that will not only broaden our understanding of the role of MYC in the field of osteoimmunology, but can also be exploited to develop therapeutic interventions to suppress bone resorption by hyperactive osteoclasts resulting from deregulated MYC expression.