# The Crosstalk between MYC and Metabolism during Osteoclastogenesis

> **NIH NIH R01** · HOSPITAL FOR SPECIAL SURGERY · 2020 · $387,200

## Abstract

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, ...

## Key facts

- **NIH application ID:** 9991747
- **Project number:** 5R01AR069562-05
- **Recipient organization:** HOSPITAL FOR SPECIAL SURGERY
- **Principal Investigator:** Kyung-Hyun Park-Min
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,200
- **Award type:** 5
- **Project period:** 2016-09-21 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991747

## Citation

> US National Institutes of Health, RePORTER application 9991747, The Crosstalk between MYC and Metabolism during Osteoclastogenesis (5R01AR069562-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9991747. Licensed CC0.

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