ReviewReview: Collagen markers in early arthritic diseases
Introduction
The two main components of articular cartilage are fibril-forming collagen type II (CII) and the cartilage specific, large proteoglycan, aggrecan [1]. CII is found exclusively in cartilagenous tissues where it constitutes over 60% of cartilage's dry weight [2]. Most of the physiological properties of cartilage are dependent on an intact CII network. These characteristics suggest that monitoring CII metabolism might provide a method for assessing the health of articular cartilage.
CII is a triple helical protein composed of three identical alpha chains. Following their synthesis, procollagen alpha chains are modified intracellularly via hydroxylation of proline and lysine residues by prolyl and lysyl hydroxylases, O-glycosylation of certain hydroxylysine residues, chain association and inter-chain disulfide bond formation to form the triple helical structure. Following secretion, the procollagen triple helix is further modified by removal of the N- and C-terminal propeptides by specific proteases, ordered arrangement of the mature fibrils and cross-linking. The helices are intra- and inter-molecularly cross-linked predominantly by hydroxylysyl pyridinoline cross-links [3], [4], a process mediated by the activity of lysyl oxidase enzyme. Two minor collagens, type IX (CIX) and type XI (CXI), join with CII in forming a heterofibril. CXI is composed of three different alpha chains and is believed to regulate fibril size. CIX [5], [6] is a FACIT collagen (fibril associated collagen with interrupted triple helices) with covalently linked proteoglycans. It constitutes around 1% of the collagen fibril and decorates its surface [7], [8].
In arthritic diseases, the stability of collagen fibrils is compromised with extensive proteolytic breakdown of CII fibrils leading to cartilage erosion and joint deterioration. Initial cleavage of CII is attributed to the collagenase sub-family of matrix metalloproteinases (MMPs) e.g. collagenase 1, 2, 3, and MT1-MMP also known as MMP-1, 8, 13, and 14, respectively [9], [10]. These collagenases preferentially cleave CII between Gly794 and Leu795 generating two fragments that are 3/4 and 1/4 the size of the collagen precursor [11]. Following initial cleavage, the triple helix of CII fragments unwind, providing a denatured substrate susceptible to further degradation by a variety of proteolytic enzymes.
Arthritic diseases are characterized by compromise of articular cartilage leading to loss of its physical properties accompanied by joint pain and loss of mobility for the patient. On gross examination, the smooth glistening articular cartilage surface becomes fibrillated progressing on to fissuring, ulceration and irreversible loss of full-thickness articular cartilage. Osteoarthritis (OA) has multiple etiologies including joint trauma [12] and genetic mutations in fibrillar collagen genes [13]. Rheumatoid arthritis (RA) is an autoimmune disorder characterized by persistent joint inflammation, polymorphonuclear cell infiltration, and synovial hyperplasia resulting in cartilage loss and joint deformity [14], [15].
The severity and progression of OA have been evaluated using magnetic resonance imaging (MRI), arthroscopy and radiographic measurement of joint space narrowing (JSN). All three techniques require a baseline measurement and a subsequent measurement after a 6 month to two year period in order to determine the rate of cartilage loss. Thus, there is a great clinical need for molecular markers which can give an instantaneous measure of the rate of joint deterioration.
Arrays of molecular markers, that reflect metabolism of cartilage and synovial tissues in OA and RA, have been investigated and validated [16], [17], [18], [19], [20], [21]. Among the most promising are markers of CII metabolism in OA and RA. Owing to its extensive and exclusive presence in cartilage, markers of CII metabolism in synovial fluid (SF), serum, and urine can reflect joint status marking the onset, and progression of OA and RA. Since alteration in CII metabolism occurs prior to detectable radiographic changes, it is a specific and early marker of arthritic joint diseases.
Cartilage components such as the telopeptides and breakdown fragments of CII diffuse into the SF. Once in the SF, they can undergo further proteolytic processing and can be cleared by the lymphatics. Some processing, particularly of carbohydrates, can occur in the lymph nodes, before entering the blood. There, further processing may occur in the liver and kidney before elimination in the urine.
The SF measurements of CII markers more directly reflect CII turnover in cartilage than either serum or urine measurements. However, SF aspiration from arthritic joints is a non-routine invasive process so routine measurements have been focused on serum and urine. To measure CII metabolism markers in arthritic diseases, immunoassays based on monoclonal or polyclonal antibodies against specific CII sequences (Fig. 1) were used to quantitate CII fragments to infer the degree of CII synthesis and degradation compared to a control population. In this review, we will focus on CII assays and their application in early detection of OA and RA.
Section snippets
Procollagen II C-propeptide
Procollagen type II C-propeptide (PIICP) undergoes specific enzymatic cleavage before incorporating CII into mature fibrils [22]. The released PIICP is composed of three 35 kDa proteins interconnected by inter-chain disulfide links [23]. The PIICP half life is relatively short approximating 16 h making it a useful index for CII synthesis both in vitro and in vivo [24]. Studies on human osteoarthritic and normal articular cartilage indicated that CII synthesis is increased in the early stages of
Other collagen markers of OA and RA
CIX, the FACIT protein that is found on the surface of CII, is accessible to the effects of proteases during the early stages of cartilage matrix degradation. Early degradation of CIX was demonstrated in a rabbit model of rheumatoid arthritis [63]. Furthermore, immuno-reactive CIX peptides were detected, by SDS-PAGE and immunoblotting, in SF from patients with RA [70]. Determination of CIX peptide fragments in biological fluids has the advantages of specifically reflecting cartilage degradation
Clinical utility of CII markers in monitoring response to therapy in cartilage degenerative diseases
Markers of CII metabolism have gained increased acceptance for evaluating the effect of drug therapies on underlying joint pathology in OA and RA. Several clinical trials were conducted using different therapies and the turnover of CII was assessed using marker assays. The effect of a daily high dose (2400 mg) of ibuprofen on the urinary levels of CTX-II levels were assessed in an OA patient population over 4–6 weeks. Compared to the placebo group which exhibited a significant elevation in
Conclusions
Deficiencies in diagnosing and monitoring OA and RA have led to investigation of molecular markers that may reflect structural changes in cartilage. The use of CII products as a marker of early disease onset and progression is now the subject of extensive research. Assays that detect markers of CII synthesis e.g. PIICP, and PIINAP, markers of CII degradation e.g. CTX-II, TIINE, CII CNBr 9.7, C2C, and CII 2-1 NO2 have been developed and validated. Most of these markers differentiate between
Acknowledgements
The authors would like to thank Dr. Ivan Otterness for his help in preparing the manuscript and his thoughtful critique.
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