I‑BET151 inhibits expression of RANKL, OPG, MMP3 and MMP9 in ankylosing spondylitis in�vivo and in�vitro

Abstract

Abstract. Ankylosing spondylitis (AS) is characterized by osteoclastogenesis and inflammatory bone resorption. The present study aimed to investigate the effect of bromodomain and extra-terminal domain (BET) protein inhibitor I-BET151 on AS process. A total of 38 AS Chinese patients were recruited and a further 38 sex-and age-matched healthy participants were selected as control. The Bath AS Function Index and Bath AS Disease Activity Index were assessed in AS patients and levels of erythrocyte sedimentation rate and C-reactive protein were measured in AS and healthy groups. Serum from AS patients was used to induce MG63 osteoblasts and BET inhibitor I-BET151 at concentrations of 50, 100 and 200 ng/ml used for treatment of the cells. A HLA-B27/β2m transgenic AS Lewis rat model was established and treated with 30 mg/kg I-BET151 for 5 weeks. Levels of receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), matrix metalloproteinase (MMP)3, and MMP9 were measured using ELISA in vivo and additionally detected with western blotting and polymerase chain reaction in vitro. The levels of RANKL, OPG, MMP3 and MMP9 were upregulated in AS serum, AS serum treated MG63 cells and HLA-B27/β2m transgenic AS rats. Conversely, levels of RANKL, OPG, MMP3 and MMP9 were significantly inhibited in cells or animals treated with I-BET151. Overall, the results of the present study demonstrated that BET inhibitor I-BET151 suppresses levels of RANKL, OPG, MMP3 and MMP9 in AS in vivo and in vitro. I-BET151 may exhibit the potential to be used as a therapeutic in the treatment of AS patients. IntroductionAnkylosing spondylitis (AS) is a kind of chronic inflammatory disease which occurs in enthuses and spine with 2 basic characteristics, osteoporosis and ankylosis of axial joints (1). Studies show that elevated levels of inflammatory cytokines and matrix metalloproteinases (MMPs) are observed in AS patients, such as tumour necrosis factors, interleukins, MMP2, MMP3 and MMP8 (2-4). Recently, signal pathway of receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) attracted scholars' attention. It was reported that increased RANKL could mediate osteoclastogenesis in AS patients or animal models (3). Moreover, bone resorption of skeleton could be protected by secreting OPG via osteoblasts. As reported, the balance of OPG and RANKL, as known as OPG/RANKL ratio, is important for maintaining normal bone metabolism. It is widely known that the OPG/RANKL ratio increases during the differentiation process of osteoblasts. In addition, upregulation of OPG/RANKL ratio has been well detected in AS patients (4-6).Bromodomain and extra-terminal domain (BET) proteins is a 'histone reading protein' class and epigenetic-related proteins (3-5,7). It was reported that BET proteins played important roles in inflammatory bone resorption and osteoclastogenesis (3-5). In addition, BET bromodomain inhibitor could reduce osteosarcoma cell proliferation and osteoblastic differentiation (8-10). It was also reported that I-BET...

Bromodomain protein inhibition: a novel therapeutic strategy in rheumatic diseases

“…The expression of these genes was also suppressed in HLA-B27/β2m transgenic AS Lewis rats, a rodent model for AS, on treatment with I-BET151. 82 Unfortunately, no other outcomes of I-BET151 were studied in this animal model. Both, JQ1 and I-BET151 were shown to exhibit protective effects on cartilage, by downregulating the expression of major factors involved in extracellular matrix degradation in human, murine and rat chondrocytes.…”

Serum Receptor Activator of Nuclear Factor-Kappa B Ligand Levels In Chinese Patients With Ankylosing Spondylarthritis: A Meta-Analysis

“…A recent study suggests that AS pathogenesis involves bone resorption and formation [42]. Although many studies have evaluated the correlation between sRANKL and AS in the Chinese population, the results are controversial [43][44][45]. Therefore, we conducted this study to investigate the association between sRANKL and AS.…”