دانلود رایگان مقاله مهار پروتئین BET و سیگنالینگ اپی ژنتیک جهت درمان پوکی استخوان

Abstract

Histone modifications are important for maintaining the transcription program. BET proteins, an important class of “histone reading proteins”, have recently been described as essential in bone biology. This study presents the therapeutic opportunity of BET protein inhibition in osteoporosis. We find that the pharmacological BET protein inhibitor JQ1 rescues pathologic bone loss in a post-ovariectomy osteoporosis model by increasing the trabecular bone volume and restoring mechanical properties. The BET protein inhibition suppresses osteoclast differentiation and activity as well as the osteoblastogenesis in vitro. Moreover, we show that treated non-resorbing osteoclasts could still activate osteoblast differentiation. In addition, specific inhibition of BRD4 using RNA interference inhibits osteoclast differentiation but strongly activates osteoblast mineralization activity. Mechanistically, JQ1 inhibits expression of the master osteoclast transcription factor NFATc1 and the transcription factor of osteoblast Runx2. These findings strongly support that targeting epigenetic chromatin regulators such as BET proteins may offer a promising alternative for the treatment of bone-related disorders such as osteoporosis.

4. Discussion

According to the world health organization, osteoporosis affects N75 million people in the United States, Europe and Japan and the lifetime risk of fracture has been estimated to be between 30 and 40% in developed countries. The treatment of this disease is considered essential to the maintenance of health and quality of life because of its morbid consequences. Emerging evidences suggest that epigenetic modulations play an important role in bone biology and may offer new targets to treat bone diseases [5,23,24]. Thus, BET proteins are a group of epigenetic regulators that bind to acetylated lysine on histone tails to regulate chromatin accessibility to transcription factors and RNA polymerase [7,8]. Numerous small-molecule were developed to target BET proteins in pre-clinical models of cancers especially in hematological malignancies [9,10,12, 25–28]. Currently, some BET protein inhibitors are being tested in early phase clinical trials illustrating the therapeutic potential of this new class of drugs (clinicaltrials.gov references NCT02157636, NCT02259114, NCT02158858 and NCT02308761). 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 [14–16]. Here we report data to support and confirm that BET protein inhibition could be a promising treatment for osteoporosis. We directly challenged an existing ovariectomy-induced osteopenia and rescued it using JQ1. This preclinical study demonstrates the potential of JQ1 as curative treatment in ovariectomized mice with established bone loss, leading to a greater trabecular bone volume (both in long bones and vertebra) associated with a greater bone strength after only 28 days of treatment. These results corroborate recent studies demonstrating that various BET protein inhibitors could increase bone mass in rheumatoid arthritis, periodontitis and osteoporosis preclinical models [14–16].