Kartogenin treatment prevented joint degeneration in a rodent model of osteoarthritis: A pilot study

Abstract

Osteoarthritis (OA) is a major degenerative joint disease characterized by progressive loss of articular cartilage, synovitis, subchondral bone changes, and osteophyte formation. Currently there is no treatment for OA except temporary pain relief and end-stage joint replacement surgery. We performed a pilot study to determine the effect of kartogenin (KGN, a small molecule) on both cartilage and subchondral bone in a rat model of OA using multimodal imaging techniques. OA was induced in rats (OA and KGN treatment group) by anterior cruciate ligament transection (ACLT) surgery in the right knee joint. Sham surgery was performed on the right knee joint of control group rats. KGN group rats received weekly intra-articular injection of 125 μM KGN 1 week after surgery until week 12. All rats underwent in vivo magnetic resonance imaging (MRI) at 3, 6, and 12 weeks after surgery. Quantitative MR relaxation measures (T_1ρ and T₂ ) were determined to evaluate changes in articular cartilage. Cartilage and bone turnover markers (COMP and CTX-I) were determined at baseline, 3, 6, and 12 weeks. Animals were sacrificed at week 12 and the knee joints were removed for micro-computed tomography (micro-CT) and histology. KGN treatment significantly lowered the T_1ρ and T₂ relaxation times indicating decreased cartilage degradation. KGN treatment significantly decreased COMP and CTX-I levels indicating decreased cartilage and bone turnover rate. KGN treatment also prevented subchondral bone changes in the ACLT rat model of OA. Thus, kartogenin is a potential drug to prevent joint deterioration in post-traumatic OA. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1780-1789, 2016.

Keywords: 7T MRI; Osteoarthritis; cartilage; kartogenin; subchondral bone.

Figure 1.

Representative articular cartilage T_1ρ and T₂ maps of sham-operated control knee joint, OA knee joint and KGN treated knee joint, 3 weeks after surgery. Maps are overlaid on Multi Gradient Echo images. The T_1ρ and T₂ values of OA group were increased compared to control group and KGN group.

Figure 2.

Effect of kartogenin on articular cartilage of OA knee joints, with the treatment started 1 week after injury. T_1ρ values of control, OA and KGN treatment group (n = 6 each) are shown for the MFC, LFC, MT, and LT. KGN treatment lowered T_1ρ values which was highly increased in the OA group. Results are reported as mean ± SD. *Control versus OA group, ^#OA versus KGN group, ⁺Control versus KGN group.

Figure 3.

Effect of kartogenin on articular cartilage of OA knee joints, with the treatment started one week after injury. T₂ values of control, OA and KGN treatment group (n = 6 each) are shown for the MFC, LFC, MT, and LT. KGN treatment lowered T_1ρ values which was highly increased in the OA group. Results are reported as mean ± SD. *Control versus OA group, ^#OA versus KGN group, ⁺Control versus KGN group.

Figure 4.

Serum COMP and CTX-I levels of the control, OA, and KGN treatment group. Both COMP and CTX-I levels were significantly increased in the OA group compared to control group and KGN treatment prevented the increased cartilage and bone turnover rate. Results are reported as mean ± SD. *Control versus OA group, ^#OA versus KGN group, ⁺Control versus KGN group.

Figure 5.

Representative sagittal micro-CT images of control, OA and KGN treated rat knee joints at 12 weeks after surgery. The OA knee joint showed altered subchondral bone architecture, and sclerosis on the medial compartment. MT of OA knee joint showed fractured subchondral plate whereas the subchondral bone was intact in the control knee joint and KGN treated knee joint.

Figure 6.

(a) Histology section of tibia from a control knee joint at 12 weeks showing normal articular cartilage without any OA-like changes in the articular cartilage. SafrninO/Fast green stained sections, original magnification × 100. (b) Histology section of tibia from an OA knee joint at 12 weeks after surgery. Articular cartilage of OA knee joint showed fibrillation, vertical fissures and delamination. The subchondral plate was fractured that lead to a cellular bone marrow, which was replaced by loosely arranged fibrous tissue surrounded by sclerotic bone as indicated by arrow. SafrninO/Fast green stained sections, original magnification × 100. (c) Histology section of tibia from a KGN treated knee joint at 12 weeks. KGN treated knee joint showed intact articular cartilage and subchondral plate, without cysts or subchondral bone loss. SafrninO/Fast green stained sections, original magnification × 100.