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

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

Figure 1

Kinetic change in (A) body weight, (B) paw volume, and (C) clinical score after immunization. The parameters were measured once every three days until day 12 and every day thereafter. There were no significant differences among the four groups (no intervention group, control; pre-arthritis intervention short group, PAS; pre-arthritis intervention long group, PAL; therapeutic intervention group, T) on all days.

Figure 2

Representative micrographs of (A) hematoxylin and eosin, and (B) safranin O-stained sagittal sections. Representative micrographs of (C) hematoxylin and eosin, and (D) safranin O-stained sagittal sections in a normal rat without treadmill running. (E) The histological scores (mean ± standard deviation) and (F) only the cartilage evaluation scored based on the histological score (mean ± standard deviation) are shown. The PAL and T groups had suppressed destruction of the ankle joint more than the control and PAS groups. ** p < 0.01, * p < 0.05. Scale bar = 200 μm. The black spot represents the position in the high-magnification figure.

Figure 3

Representative micrographs of immunohistochemical staining for (A) TNF-α and (B) Cx43 are shown. All images were evaluated semi-quantitatively using ImageJ for (C) TNF-α and (D) Cx43. T group had significantly suppressed TNF-α and Cx43 expression. * p < 0.05. Scale bar = 200 μm. The black spot represents the position in the high-magnification figure.

Figure 4

Representative three-dimensional reconstruction of (A) the sagittal sections of the talus architecture. Trabecular bone parameters such as (B) bone volume fraction (BV/TV), (C) trabecular thickness (Tb.Th), (D) bone mineral content per tissue volume (BMC/TV), and (E) marrow star volume (MSV) of the whole talus are shown. T group had improved bone loss. n = 4 in each group. * p < 0.05.

Figure 5

(A) Representative micrographs of cathepsin K immunohistochemical staining. Cathepsin K positive cells were fewer in the PAL and T groups. (B) Representative 3D reconstruction of bone erosion area in the whole talus architecture. Red area is bone erosion area. (C) The eroded bone surface (Es) and repaired bone surface (Rps) was calculated using 3D-μ-CT, and Es/Rps values are shown for the four groups. Es/Rps was significantly lower in the T group compared to the control group. * p < 0.05. Scale bar = 200 μm. The black spot represents the position in the high-magnification figure.

Figure 6

Experimental protocols. Eight-week-old male Dark Agouti rats were randomly divided into four groups: control, PAS, PAL, and T groups. PAS (n = 8), run from day 14 to 28; PAL (n = 8), run from day 14 to 42; and T (n = 8), run from day 28 to 42.