The Crosstalk between MYC and Metabolism during Osteoclastogenesis

类风湿关节炎(RA)是一种慢性炎症性疾病，免疫细胞和滑膜成纤维细胞 产生促炎细胞因子，并推动炎症状态，从而破坏受影响的 关节。骨侵蚀是类风湿关节炎的诊断标志，通常先于临床的发展。 症状。破骨细胞是一种髓系细胞，可以有效地吸收骨骼，并直接负责 类风湿性关节炎的骨质侵蚀和发病率。因此，我们的总体假设是，对监管的更好理解 破骨细胞分化和活性的研究可能为限制病理性骨的治疗提供新的靶点 再吸收。我们发现转录因子MYC和依赖于MYC的转录程序是 在破骨细胞分化早期被RANKL激活。尽管MYC被牵连到 破骨细胞生成，MYC影响内稳态和功能的确切机制 破骨细胞在很大程度上仍未被发现。我们发现MYC是破骨细胞分化所必需的，而且 调节破骨细胞形成过程中与新陈代谢和翻译相关的基因。 有趣的是，MYC和NFATc1在滑膜破骨细胞前体细胞中的表达显著升高 (OCP)来自RA患者，具有更大的分化为破骨细胞的潜力。OCP是 认为重新编程它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以吸收骨。然而，新陈代谢的贡献 破骨细胞分化的途径和调节代谢重编程的关键分子不是 很好理解。因此，我们推测MYC在RANKL诱导的代谢中起重要作用。 重新编程和MYC是在炎症性疾病中产生过度活跃的破骨细胞的主要因素之一 通过改变特定的新陈代谢途径导致骨骼疾病。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在体内破骨细胞形成中的作用；2)确定其分子机制 了解MYC的调节和功能，以及3)研究MYC的调节机制 破骨细胞的代谢重编程。这项研究将促进我们对MYC在 破骨细胞分化，在破骨细胞分化过程中代谢重新编程的作用 在破骨细胞形成过程中MYC和代谢重编程之间的串扰。此外，作为治疗方法， 直接靶向MYC激活目前尚不能用于临床，效应分子的鉴定(S) 在破骨细胞分化中起重要作用的MYC下游基因可能成为新的治疗方法 治疗和预防病理性骨吸收的靶点。因此，这一点的总体影响 该项目的目的是提供见解，不仅将扩大我们对MYC在以下领域的作用的理解 骨免疫学，但也可以用来开发抑制骨吸收的治疗干预措施 由MYC表达失控引起的过度活跃的破骨细胞所致。

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.