Selective Targeting of Bromodomains of the Bromodomain-PHD Fingers Family Impairs Osteoclast Differentiation

Histone acetylhansferases of the MYSTfainily ate recruited to chromatin by BRPP scaffolding proteins. We explored functional consequences and the therapeutic potential of inhibitors targeting acetyl-lysine-dependent protein interaction domains (bromodomains) present in BRPF1-3 in bone Maintenance. We report three potent and selective inhibitors: one (PEI-4) with high selectivity for the BRPFIB isoform and two pan-BRPF bromodomain inhibitors (OF-1, NI-57). The developed inhibitors displaced BRPF bromodomains from chromatin and did not inhibit cell growth and proliferation. Intriguingly, the inhibitors impaired RANKL-indueed differentiation of primary murine bone marrow cells and human primary monocytes into bone resorbing osteoclasts by specifically repressing transcriptional programs required for osteoclastogenesis. The data suggest a key role of BRPF in regulating gene expression during osteoclastogenesis, and the excellent druggability of these bromodomains may lead to new treatment strategies for patients suffering from bone loss or osteolytic malignant bone lesions.