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.
Bone erosion is one of the key features in the development and exacerbation of chronic inflammatory diseases, such as rheumatoid arthritis. Osteoclasts are the specific cells that cause bone erosion, and this work explores new mechanisms whereby osteoclasts can be regulated. By deterring the development and activation of osteoclasts in inflammatory settings, we can hinder bone erosion and therefore prevent disease development.
| Park-Min, Kyung-Hyun (2018) Mechanisms involved in normal and pathological osteoclastogenesis. Cell Mol Life Sci 75:2519-2528 |
| Bae, Seyeon; Lee, Min Joon; Mun, Se Hwan et al. (2017) MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERR?. J Clin Invest 127:2555-2568 |
| Park-Min, Kyung Hyun (2017) Epigenetic regulation of bone cells. Connect Tissue Res 58:76-89 |
| Murata, Koichi; Fang, Celestia; Terao, Chikashi et al. (2017) Hypoxia-Sensitive COMMD1 Integrates Signaling and Cellular Metabolism in Human Macrophages and Suppresses Osteoclastogenesis. Immunity 47:66-79.e5 |
