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Review
. 2011 Apr 28;13(2):215.
doi: 10.1186/ar3280.

Biochemical markers of ongoing joint damage in rheumatoid arthritis--current and future applications, limitations and opportunities

Morten A Karsdal  1 , Thasia Woodworth, Kim Henriksen, Walter P Maksymowych, Harry Genant, Philippe Vergnaud, Claus Christiansen, Tanja Schubert, Per Qvist, Georg Schett, Adam Platt, Anne-Christine Bay-Jensen
Affiliations
Review

Biochemical markers of ongoing joint damage in rheumatoid arthritis--current and future applications, limitations and opportunities

Morten A Karsdal et al. Arthritis Res Ther. .

Abstract

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease associated with potentially debilitating joint inflammation, as well as altered skeletal bone metabolism and co-morbid conditions. Early diagnosis and aggressive treatment to control disease activity offers the highest likelihood of preserving function and preventing disability. Joint inflammation is characterized by synovitis, osteitis, and/or peri-articular osteopenia, often accompanied by development of subchondral bone erosions, as well as progressive joint space narrowing. Biochemical markers of joint cartilage and bone degradation may enable timely detection and assessment of ongoing joint damage, and their use in facilitating treatment strategies is under investigation. Early detection of joint damage may be assisted by the characterization of biochemical markers that identify patients whose joint damage is progressing rapidly and who are thus most in need of aggressive treatment, and that, alone or in combination, identify those individuals who are likely to respond best to a potential treatment, both in terms of limiting joint damage and relieving symptoms. The aims of this review are to describe currently available biochemical markers of joint metabolism in relation to the pathobiology of joint damage and systemic bone loss in RA; to assess the limitations of, and need for additional, novel biochemical markers in RA and other rheumatic diseases, and the strategies used for assay development; and to examine the feasibility of advancement of personalized health care using biochemical markers to select therapeutic agents to which a patient is most likely to respond.

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Figures

Figure 1
Figure 1
Cells involved in rheumatoid arthritis joint damage include osteoblasts, osteoclasts, chondrocytes, monocytes/macrophages, B cells, T cell subsets (including regulatory T cells), and fibrobast-like synoviocytes, each playing distinct complex and interrelated roles in its pathogenesis and progression. This cellular diversity highlights the need for biomarkers for a range of pathological events. Different markers of cell signaling (for example, receptor activator of NF-kB ligand (RANKL) and osteoprotegerin (OPG)), cell differentiation, collagen I and II degradation and turnover, matrix production, and matrix degradation and the enzymes mediating that degradation may be measured. The pleiotrophic cytokines IL-1β, TNF-α, IL-6, and IL-17, as well as several other cytokines and chemokines, are associated with the induction of matrix metalloproteinases (MMPs), as well as osteoclast differentiation, activation and release of cathepsin K [36]. This range of interactive events leads to progressive joint destruction if not managed attentively, for example, using tight control strategies [15,18,22,104,140,141]. C2C, type II collagen fragment; CIIM, MMP mediated type II collagen degradation; CTX-I, C-terminal telopeptide of collagen type I; CTX-II, C-terminal telopeptide of collagen type II.
Figure 2
Figure 2
A graphic representation of the generation of pathology-relevant neoepitopes of inflamed joint cartilage. The enzymes presently receiving the most attention are the matrix metalloproteinases (MMPs) and aggrecanases (ADAM-TS (a disintegrin and metalloproteinase with thrombospondin motifs)). The most abundant cartilage proteins are collagen type II and aggrecan. Protease-generated fragments of collagen type II and aggrecan produced through the action of these important enzymes, which may be relevant molecules in tissue destruction, can be used to monitor tissue turnover. These fragments, such as C-terminal telopeptide of type II collagen (CTX-II), may be used in clinical settings, in preclinical models and in simple ex vivo and in vitro systems. Figure adapted with permission from [8].
Figure 3
Figure 3
Protease-generated neoepitopes in aggrecan and collagen type I and II. (a,b) The amino- and carboxy-terminal pro-peptides PINP (amino terminus propeptide of type I procollagen), PICP (carboxyl terminus propeptide of type I procollagen), PIINP (amino terminus propeptide of type II procollagen) and PIICP (carboxyl terminus propeptide of type II procollagen) in collagen type I (a) and collagen type II (b) are used to define protein formation, as they are released during formation of the matrix. (a) In contrast, the degradation markers ICTP (type I collagen; MMP mediated) and C-terminal telopeptide of type I collagen (CTX-I; cathepsin-K mediated) located in the carboxy-terminal telopeptide are found in body fluids after degradation of collagen type I. (b) The CTX-II (MMP mediated) degradation marker is located in the carboxy-terminal telopeptide in collagen type II. Coll 2-1, TIINE, C2C, and C2-3/4C are degradation markers located in the helix of collagen type II. (c) The aggrecan molecule is shown with the MMP cleavage sites (upward arrows) and ADAM-TS (a disintegrin and metalloproteinase with thrombospondin motifs) cleavage sites (downward arrows). CIIM is a novel MMP mediated type II collagen degradation marker [142]. Figure adapted with permission from [8].
Figure 4
Figure 4
Biochemical markers provide increased sensitivity to change compared with imaging techniques assessing joint space width (JSW). Figure adapted with permission from [16].
Figure 5
Figure 5
In bone, cell activation, cell differentiation, matrix production, matrix degradation and the enzymes mediating that degradation may be measured by different markers. Each marker provides unique information and may indicate both pathological aspects and serve as a surrogate measure of the mode of action and potential efficacy of therapeutic interventions [85]. BSAP, bone specific alkaline phosphatase; CTX, C-terminal telopeptide of collagen; ICTP, collagen type I fragment; NTX, N-terminal telopeptide of collagen type I; OC, osteocalcin; OPG, osteoprotegerin; PICP, carboxyl terminus propeptide of type I procollagen; PINP, amino terminus propeptide of type I procollagen; RANK, receptor activator of NF-kB; RANKL, receptor activator of NF-kB ligand. Figure adapted with permission from [85].
Figure 6
Figure 6
Schematic of the use and interpretation of biochemical markers. (a) Rheumatoid arthritis (RA) may consist of many different subphenotypes, with similarities and dissimilarities, as illustrated by the overlap and non-overlap of the different colored circles. If this population is left unsegmented, and the population treated as a whole, a relatively low number of responders may be identified. (b) A biomarker combination may identify a subset of patients representing a given phenotype that will respond to treatment, or respond preferentially to a particular therapeutic intervention, increasing overall response rates. (c,d) Different questions can be addressed by the use of biochemical markers. Each may require a different biomarker subset. (c) Prognostic markers are those able to predict which patients will progress most rapidly. This is important for identifying those patients most in need of treatment. (d) A marker of efficacy will allow interpretation of potential efficacy far earlier than traditional radiological-based changes.
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