p300/CBP inhibitor A-485 inhibits the differentiation of osteoclasts and protects against osteoporotic bone loss.

Abstract

Osteoporosis is one of the most common metabolic bone diseases among pre- and post-menopausal women. Despite numerous advances in the treatment of osteoporosis in recent years, the outcomes remain poor due to severe side effects. In this study, we investigated whether A-485, a highly selective catalytic p300/CBP inhibitor, could attenuate RANKL-induced osteoclast differentiation and explored the underlying molecular mechanisms. The protective role of A-485 in osteoporosis was verified using a mouse model of ovariectomy (OVX)-induced bone loss and micro-CT scanning. A-485 inhibited RANKL-induced osteoclast differentiation in vitro by reducing the number of tartrate-resistant acid phosphatase-positive osteoclasts without inducing significant cytotoxicity. In particular, A-485 dose-dependently disrupted F-actin ring formation and downregulated the expression of genes associated with osteoclast differentiation, such as CTSK, c-Fos, TRAF6, VATPs-d2, DC-STAMP, and NFATc1, in a time- and dose-dependent manner. Moreover, A-485 inhibited the RANKL-induced phosphorylation of MAPK pathways and attenuated OVX-induced bone loss in the mouse model while rescuing the loss of bone mineral density. Our in vitro and in vivo findings suggest for the first time that A-485 has the potential to prevent postmenopausal osteoporosis and could therefore be considered as a therapeutic molecule against osteoporosis.

• Authors: Shicheng Huo, Xuesong Liu, Shutao Zhang, Zhuocheng Lyu, Jue Zhang, You Wang, Bin'en Nie, Bing Yue
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 94 Pg. 107458 (May 2021) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 33626422 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• A-485 compound
• Bone Density Conservation Agents
• Heterocyclic Compounds, 4 or More Rings
• Membrane Proteins
• Pag1 protein, mouse
• Phosphoproteins
• E1A-Associated p300 Protein
• Ep300 protein, mouse

Topics

• Animals
• Bone Density Conservation Agents (pharmacology, therapeutic use)
• Bone Resorption (drug therapy)
• Cell Differentiation (drug effects)
• Cell Line
• E1A-Associated p300 Protein (antagonists & inhibitors)
• Female
• Heterocyclic Compounds, 4 or More Rings (pharmacology, therapeutic use)
• Membrane Proteins (antagonists & inhibitors)
• Mice, Inbred C57BL
• Osteoclasts (drug effects, physiology)
• Osteoporosis (drug therapy)
• Ovariectomy
• Phosphoproteins (antagonists & inhibitors)
• Rats