Peficitinib improves bone fragility by recovering bone turnover imbalance in arthritic mice

• Published in: Journal of pharmacological sciences Vol. 148; no. 1; pp. 134 - 141
• Main Authors: Sugahara, Shingo, Hanaoka, Kaori, Emori, Takashi, Takeshita, Nobuaki, Fujii, Yasutomo, Nakano, Masaki, Suzuki, Takako, Takahashi, Jun, Nakamura, Yukio
• Format: Journal Article
• Language: English
• Published: Japan Elsevier B.V 01.01.2022; Elsevier
• Subjects: Adamantane - analogs & derivatives; Adamantane - pharmacology; Adamantane - therapeutic use; Animals; Arthritis; Arthritis, Rheumatoid - complications; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - metabolism; Bone and Bones - metabolism; Bone density; Bone Density - drug effects; Bone Remodeling - drug effects; Bone Resorption - prevention & control; Disease Models, Animal; Janus Kinase Inhibitors - pharmacology; Janus Kinase Inhibitors - therapeutic use; Male; Mice; Mice, Inbred DBA; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Niacinamide - therapeutic use; Osteoblasts - metabolism; Osteoclast/osteoblast biology; Osteoporosis; Osteoporosis - drug therapy; Osteoporosis - etiology; Osteoporosis - prevention & control; Peficitinib; RANK Ligand - metabolism; Osteoporosis; Arthritis; Bone density; Osteoclast/osteoblast biology; Peficitinib
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1016/j.jphs.2021.10.006

Peficitinib, a pan-JAK inhibitor, is known to suppress the activation of fibroblast-like synoviocytes (FLSs) and thereby reduces joint inflammation associated with rheumatoid arthritis (RA). However, the effect on osteoporosis in RA remains to be elucidated. In this study, the effect of peficitinib or etanercept on joint inflammation, and consequently decreased bone mineral density (BMD) was evaluated in mice with collagen-induced arthritis (CIA). Additionally, the effect on RANKL production from osteoblasts differentiated from the mesenchymal stem cells of RA patients was evaluated. Administration of peficitinib for established CIA ameliorated arthritis and improved BMD in the femoral metaphysis, but not in the femoral diaphysis. Conversely, etanercept suppressed an increase in synovial inflammatory markers but did not improve arthritic conditions or the reduction of BMD in either region. All elevated bone formation and bone resorption markers were decreased with peficitinib but only partially decreased with etanercept. Furthermore, production of RANKL by human osteoblasts was suppressed by peficitinib but enhanced by etanercept. Unlike etanercept, peficitinib is thought to increase BMD by ameliorating the high bone turnover associated with RA states, resulting in improvement of bone fragility. Our data provide evidence that peficitinib would be expected to show efficacy for osteoporosis associated with RA.