Selective Targeting of Bromodomains of the Bromodomain-PHD Fingers Family Impairs Osteoclast Differentiation.
Meier JC., Tallant C., Fedorov O., Witwicka H., Hwang S-Y., van Stiphout RG., Lambert J-P., Rogers C., Yapp C., Gerstenberger BS., Fedele V., Savitsky P., Heidenreich D., Daniels DL., Owen DR., Fish PV., Igoe NM., Bayle ED., Haendler B., Oppermann UCT., Buffa F., Brennan PE., Müller S., Gingras AC., Odgren PR., Birnbaum MJ., Knapp S.
Histone acetyltransferases of the MYST family are recruited to chromatin by BRPF 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 (PFI-4) with high selectivity for the BRPF1B 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-induced 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.