*Article* **Treadmill Running in Established Phase Arthritis Inhibits Joint Destruction in Rat Rheumatoid Arthritis Models**

**Yuta Fujii 1, Hiroaki Inoue 1, Yuji Arai 2,\*, Seiji Shimomura 1, Shuji Nakagawa 2, Tsunao Kishida 3, Shinji Tsuchida 1, Yoichiro Kamada 1, Kenta Kaihara 1, Toshiharu Shirai 1, Ryu Terauchi 1, Shogo Toyama 1, Kazuya Ikoma 1, Osam Mazda <sup>3</sup> and Yasuo Mikami <sup>4</sup>**


Received: 13 September 2019; Accepted: 13 October 2019; Published: 15 October 2019

**Abstract:** Exercise therapy inhibits joint destruction by suppressing pro-inflammatory cytokines. The efficacy of pharmacotherapy for rheumatoid arthritis differs depending on the phase of the disease, but that of exercise therapy for each phase is unknown. We assessed the differences in the efficacy of treadmill running on rheumatoid arthritis at various phases, using rat rheumatoid arthritis models. Rats with collagen-induced arthritis were used as rheumatoid arthritis models, and the phase after immunization was divided as pre-arthritis and established phases. Histologically, the groups with forced treadmill running in the established phase had significantly inhibited joint destruction compared with the other groups. The group with forced treadmill running in only the established phase had significantly better bone morphometry and reduced expression of connexin 43 and tumor necrosis factor α in the synovial membranes compared with the no treadmill group. Furthermore, few cells were positive for cathepsin K immunostaining in the groups with forced treadmill running in the established phase. Our results suggest that the efficacy of exercise therapy may differ depending on rheumatoid arthritis disease activity. Active exercise during phases of decreased disease activity may effectively inhibit arthritis and joint destruction.

**Keywords:** rheumatoid arthritis; exercise therapy; autoimmune disorder; treadmill running; exercise; articular cartilage; collagen-induced arthritis; pro-inflammatory cytokine; connexin 43; osteoporosis
