Inhibition of osteoclastogenesis and inflammatory bone resorption by targeting BET proteins and epigenetic regulation

Abstract

Emerging evidence suggests that RANKL-induced changes in chromatin state are important for osteoclastogenesis, but these epigenetic mechanisms are not well understood and have not been therapeutically targeted. In this study we find that the small molecule I-BET151 that targets bromo and extra-terminal (BET) proteins that “read” chromatin states by binding to acetylated histones strongly suppresses osteoclastogenesis. I-BET151 suppresses pathologic bone loss in TNF-induced inflammatory osteolysis, inflammatory arthritis, and post-ovariectomy models. Transcriptome analysis identifies a MYC-NFAT axis important for osteoclastogenesis. Mechanistically, I-BET151 inhibits expression of the master osteoclast regulator NFATC1 by suppressing expression and recruitment of its newly identified upstream regulator MYC. MYC is elevated in rheumatoid arthritis and its induction by RANKL is important for osteoclastogenesis and TNF-induced bone resorption. These findings highlight the importance of an I-BET151-inhibited MYC-NFAT axis in osteoclastogenesis, and suggest targeting epigenetic chromatin regulators holds promise for treatment of inflammatory and estrogen deficiency-mediated pathologic bone resorption.

Bromodomain and Extra-terminal (BET) Protein Inhibitors Suppress Chondrocyte Differentiation and Restrain Bone Growth

“…Besides bone formation, bone homeostasis is maintained by the balance between osteoblastic bone formation and osteoclastic bone resorption, whereas the growth of long bones is from endochondral ossification of chondrocytes derived from cartilage (15). Previous studies have shown that BET inhibitors may affect osteoclastogenesis (14) and the bone-associated tumor vicious cycle (13). In this study, we demonstrated BET inhibitors as repressors of chondrogenesis.…”

“…Pharmacological inhibition of BET proteins lowers the expression of key transcription factors such as oncogene c-MYC (8), clamps the transductions of PI3K signaling (9), inhibits Gli1 transcription and Hedgehog pathway (10), blocks transcription in neurons (11), represses VEGF-induced angiogenesis and vascular permeability (12), reduces cell viability of osteosarcoma cells and inhibits osteoblastic differentiation (13), and restrains osteoclastogenesis (14). Meanwhile, potent BET inhibitors have been identified as showing antitumor efficacy in a number of preclinical cancer models in recent years, including leukemia, multiple myeloma, lymphoma, melanoma, and gastric cancer (15,16).…”

Inhibition of BET proteins and epigenetic signaling as a potential treatment for osteoporosis

“…In this context, we recently showed that, JQ1, one of the BET protein inhibitor was able to suppress osteosarcoma mediated bone remodeling in a preclinical model [11]. Since then, several studies have shown that BET protein inhibition seems to be a potential candidate for the treatment of bone related diseases associated with inflammation [14][15][16].…”

“…In addition, these smallmolecule inhibitors of BET proteins were recently identified to suppress bone destruction in many distinct inflammatory diseases (arthritis, periodontitis, bone tumour, osteoporosis) [11,[14][15][16].…”

“…demonstrating that various BET protein inhibitors could increase bone mass in rheumatoid arthritis, periodontitis and osteoporosis preclinical models [14][15][16].…”