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Updated: Nov 1, 2025

A Novel in vivo Gene Transfer Technique and in vitro Cell Based Assays for the Study of Bone Loss in Musculoskeletal Disorders
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A novel BRD4 inhibitor suppresses osteoclastogenesis and ovariectomized osteoporosis by blocking RANKL-mediated MAPK

Ying Liu1, Wenjie Liu2, Ziqiang Yu1

  • 1Institute of Translational Medicine, Shanghai University, 99 Shangda Road, Shanghai, 200444, China.

Cell Death & Disease
|June 27, 2021
PubMed

Insights

A new compound, (+)-ND, effectively inhibits bone loss by targeting bromodomain-containing protein 4 (BRD4). This chiral derivative shows promise for treating osteoporosis by suppressing osteoclast activity and preventing bone degradation.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Orthopedics

Background:

  • Bromodomain-containing protein 4 (BRD4) is a key target for bone disorders.
  • (+)-JQ1 inhibits osteoclast activity and bone loss but has poor druggability.
  • Chirality is crucial for the biological activity of BRD4 inhibitors.

Purpose of the Study:

  • To synthesize and evaluate novel (+)-JQ1 derivatives with improved druggability.
  • To investigate the role of chirality in the anti-osteoclastic activity of (+)-JQ1 analogues.
  • To assess the therapeutic potential of (+)-ND in osteoporosis models.

Main Methods:

  • Synthesis of a new chiral (+)-JQ1 derivative, (+)-ND.
  • In vitro assays measuring BRD4 inhibition, osteoclastogenesis, and bone resorption.
  • In vivo studies using an ovariectomy (OVX)-induced osteoporosis mouse model.

Main Results:

  • (+)-ND demonstrated higher solubility and potent BRD4 inhibition compared to (+)-JQ1.
  • The (+) enantiomers ((+)-JQ1 and (+)-ND) were significantly more effective than (-) enantiomers in inhibiting osteoclastogenesis.
  • (+)-ND suppressed osteoclast-specific gene expression, F-actin ring formation, and bone resorption in vitro, and prevented bone loss in OVX mice.

Conclusions:

  • (+)-ND effectively represses RANKL-stimulated osteoclastogenesis and averts OVX-triggered osteoporosis.
  • The compound acts by suppressing MAPK and NF-κB signaling pathways.
  • (+)-ND is a promising therapeutic candidate for osteoporosis treatment.

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