Joint Degradation in a Monkey Model of Collagen-Induced Arthritis: Role of Cathepsin K Based on Biochemical Markers and Histological Evaluation.

Makoto Tanaka,Satoshi Nishikawa,Naoto Horai,Minqi Li,Hiroshi Mori,Hiroyuki Yamada,Yasuo Ochi,Norio Amizuka

doi:10.1155/2016/8938916

Abstract

The role of cathepsin K in joint degradation in a model of collagen-induced arthritis (CIA) in cynomolgus monkey was examined using biochemical markers and histology. Joint swelling, urinary C-telopeptide of type II collagen (CTX-II), deoxypyridinoline (DPD), and N- and C-telopeptides of type I collagen (NTX and CTX-I, resp.) were analyzed. Immunohistochemistry of type II collagen, cathepsin K, and CTX-II were performed using joints. Joint swelling reached peak on day 42 and continued at this level. The CTX-II level peaked on day 28 and declined thereafter, while CTX-I, NTX, and DPD reached plateau on day 43. Joint swelling was positively correlated with CTX-II increases on days 20 and 42/43, with increases in CTX-I and NTX/Cr on days 42/43 and 84, and with DPD increases throughout the study period. Intense cathepsin K staining was observed in osteoclasts and in articular cartilage and synovial tissue in arthritic joints. CTX-II was present in the superficial layer of articular cartilage in CIA monkeys. Evidence from biochemical markers suggests that matrix degradation in the CIA model starts with degradation of cartilage, rather than bone resorption. Cathepsin K expressed in osteoclasts, articular cartilage, and synovial tissue may contribute to degradation of cartilage.

Highlights

Rheumatoid arthritis (RA) is characterized by chronic inflammation of synovial joints leading to periarticular bone loss/erosion and cartilage destruction, which cause reduced function and poorer quality of life [1, 2]
area under the concentration/score curve (AUC) of the cartilage marker (CTX-II/Cr) and all bone resorption markers were positively correlated with the joint swelling score, which suggests that matrix degradation may be regulated by the degree of joint inflammation (Table 1)
A key finding in this study of longitudinal changes in a monkey collagen-induced arthritis (CIA) model was that joint damage starts with cartilage degradation in the most superficial layer of articular cartilage, rather than through bone resorption, and is coupled with a transient increase in the urinary cartilage marker C-telopeptide of type II collagen DPD (CTX-II)

Summary

Introduction

Rheumatoid arthritis (RA) is characterized by chronic inflammation of synovial joints leading to periarticular bone loss/erosion and cartilage destruction, which cause reduced function and poorer quality of life [1, 2]. Bone loss is caused by a relative increase in bone resorption mediated by osteoclasts over bone formation mediated by osteoblasts [3]. Elevation of inflammatory cytokines such as tumor necrosis factor alpha and interleukin-1 promotes cell differentiation of the Th17 cell subset and induces osteoclastogenesis in RA [4]. Antiresorption agents are effective in preventing bone loss, but not disease suppression, in clinical studies of RA [5, 6]. Cartilage degradation appears to be a result of proteolysis of extracellular matrix. Matrix metalloproteinases have been considered as a potent target for the treatment of RA, but the therapeutic efficacy of matrix metalloproteinase inhibitors is not verified

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Conclusion