Session Title: Biology and Pathology of Bone and Joint (Bone and Arthritis)
Session Type: Abstract Submissions (ACR)
Background/Purpose: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by leukocyte infiltration, synoviocyte hyperplasia and osteoclastogenesis, leading to erosion of the joints and cartilage, which results in stiffness, pain and swelling, making it difficult to perform daily activities. Osteoclasts are responsible for bone erosion in RA and both Bruton’s tyrosine kinase (Btk) and Tec kinase have essential functions in osteoclast differentiation. ONO-4059 is a highly potent and dual oral Btk/Tec inhibitor with an IC50 in the sub-nmol/L range. Previous studies with ONO-4059 demonstrated that ONO-4059 significantly inhibits the macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL)-driven osteoclast defferentiation. The treatment with ONO-4059 also resulted in a dose-dependent inhibition of arthritis severity and bone damage in a mouse collagen induced arthritis (CIA) model (ACR 2012). To assess the effects of ONO-4059 on bone resorption, we examined the RANKL-induced bone loss in vivo. In addition, the regulation of proinflammatory cytokines and MMPs in the joints of arthritic mice validating qRT-PCR was performed in another CIA model.
Methods: Female C57BL/6 mice were injected intraperitoneally with 1 mg/kg of sRANKL on days 0, 1 and 2. ONO-4059 was administered orally, twice a day in three groups of animals, at doses of 3 mg/kg, 10 mg/kg and 30 mg/kg 1 hr before the every sRANKL injection. After the last sRANKL injection, all of the mice were sacrificed and underwent peripheral quantitative computed tomograghy (pQCT) analysis. To further characterize the effect of ONO-4059 in a RANKL-induced model, the serum bone resorption markers were measured by ELISA. Gene expression profiles were determined by qPCR using samples taken from the ankle in CIA model.
Results: The injection of sRANKL resulted in a decrease in trabecular bone volume with the increase of serum TRACP5β and CTX-1. Treatment with ONO-4059 resulted in a dose-dependent suppressioin of RANKL-induced bone loss with the inhibition of TRACP5β and CTX-1. The inhibition rate of Bone Mineral Density (BMD) of ONO-4059-treated animals was 55% (P<0.05), 87% (P<0.001) and 88% (P<0.001) for the 3, 10 and 30 mg/kg dose groups respectively. In CIA model, MIP-1α, IL-1β, KC, IL-6, RANKL and MMP-3 production in joints of arthritic mice, as measured by determining relative arthritic/sham ratios, was significantly higher (from 5 to 20 fold), while the 3 mg/kg dose of ONO-4059 almost completely inhibited such production.
Conclusion: Btk and Tec are required for osteoclast differentiation and activation based on the genetic evidence obtained from Btk and Tec double deficient mice. Dual Btk/Tec inhibitor, ONO-4059 may be a novel therapeutic target for RA to suppress bone erosion and inflammation.
« Back to 2013 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/ono-4059-a-novel-small-molecule-dual-inhibitor-of-brutons-tyrosine-kinase-btk-and-tec-kinase-suppresses-osteoclastic-bone-resorption-and-inflammation/