Biochemical Markers of Joint Tissue Turnover

REVIEW

Biochemical Markers of Joint Tissue Turnover

Anne-Christine Bay-Jensen, Bodil Cecilie Sondergaard, Claus Christiansen, Morten A. Karsdal, Suzi Høgh Madsen, and Per Qvist Nordic Bioscience A/S, Herlev, Denmark.

In this report, we aim to provide a brief and general overview of bone, cartilage, and synovium markers currently available for clinical and research use, and in particular we highlight recent studies investigating biochemical markers in OA. Finally, we provide perspectives on the possible enhancements on future drug development with better use of biomarker information.

ABSTRACT

BIOCHEMICAL MARKERS OF JOINT TISSUE

Recent disappointments in late stage developments of anti-osteoarthritic drugs have reinforced efforts to develop better biomarkers for application in both the drug development process as well as in the routine management of these patients. Here we provide a brief review of biochemical tests available for the study of tissue turnover in each of the three compartments of the articular joint, that is the bone, the cartilage, and the synovium. Finally, we provide some perspective to future developments in biomarker discovery and discuss the potential impact such technologies could have on the drug development process.

Application of biochemical markers in the study of osteoarthritis (OA) has attracted much attention, and the field has been the subject of several reviews over the last several years.2–7 The joint has three major compartments: the bone, the articular cartilage, and the synovium; and all three are affected by the disease,8 which manifests as osteophyte formation, subchondral sclerosis, articular cartilage breakdown, and alterations of the synovium such as inflammation, proliferation, and synovial thickening.

Cartilage

INTRODUCTION

O

bviously, the road to the identification and the clinical demonstration of both efficacy and safety of the chondroprotective drug is paved with numerous obstacles. Over the last few years, the disappointments associated with efforts to develop a disease modifying osteoarthritis drug (DMOAD) have been numerous and still today the millions of patients suffering from the serious, chronic disease can only be offered treatments aimed at improving signs and symptoms of the disease. This huge, unmet medical need has been the primary driver behind major efforts to develop improved analytical techniques allowing better and more efficient clinical trial design and implementation.1

A central hallmark in OA pathogenicity is a gradual destruction of articular cartilage and local denudation leading to loss of joint function.9 The turnover of cartilage is normally maintained by a balance between catabolic and anabolic processes; however, in the case of pathological matrix destruction, the rate of cartilage degradation exceeds the rate of formation, resulting in a net loss of cartilage matrix.10,11 During degradation of articular cartilage, matrix metalloproteinases (MMPs) and aggrecanases are considered the most important proteases for degradation of articular cartilage.10,12–14 Cartilage is a nonvascularized tissue consisting of chondrocytes and extracellular matrix (ECM). The ECM is a composite network of proteins, that is primarily collagens,15 interacting with polysaccharides and proteoglycans. While collagen type II is the

ABBREVIATIONS: CI, confidence interval; COMP, cartilage oligomeric matrix protein; CTX-I, C-telopeptide of type I collagen; CTX-II, C-telopeptide of type II collagen; DMOAD, disease modifying osteoarthritis drug; ECM, extracellular matrix; ELISA, enzyme-linked immunosorbent assay; HA, hyaluronic acid; ICTP, cross-linked telopeptides of type I collagen; mAb, monoclonal antibody; MMP, matrix metalloproteinase; NTX-I, N-telopeptide of type I collagen; OA, osteoarthritis; PICP, C-terminal propeptide of type I procollagen; PIIANP, N-terminal propeptide of type II procollagen, splice variant A; PIINP, N-terminal propeptide of type II procollagen; PINP, N-terminal propeptide of type I procollagen; RA, rheumatoid arthritis; WOMAC, Western Ontario and McMaster Osteoarthritis Index.

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DOI: 10.1089/adt.2009.0199

BIOCHEMICAL MARKERS OF JOINT TISSUE TURNOVER

most abundant collagen in articular cartilage, aggrecan is the predominant proteoglycan. Other important molecules in articular cartilage include cartilage oligomeric matrix protein (COMP), link protein, and hyaluronan (or hyaluronic acid). In a longitudinal intervention study of diacerein, Mazieres and coworkers found by multivariate analysis that Hyaluronic acid (HA) and C-telopeptide of type II collagen (CTX-II), the latter generated by cleavage with MMPs, were significantly (both P < 0.0001) associated with radiographic progression of knee OA. With HA or CTX-II in the highest tertile, the relative risk for progression was 1.69 (95% confidence interval (CI), 1.25–2.27) and 2.00 (95% CI, 1.49–2.70), respectively, compared to the two lowest tertiles.16 This association remained significant after adjustment for baseline clinical, radiological, and treatment variables, and as the two biomarkers were independent, patients with both markers in the highest tertile had a relative risk of progression of 3.73 (95% CI, 2.48–5.61) compared to the two lowest tertiles. In addition, association with disease progression has been reported for in a few other studies, for example, for CTX-II,17,18 COMP,19 and type IIA procollagen amino terminal propeptide (PIIANP).20 In a recent study of oral salmon calcitonin, daily doses of 1 mg induced a significant reduction in both function and pain scores above placebo at days 42 and 84 in subjects with knee OA.21 At day 84, urinary levels of a series of biomarkers, including CTX-II, MMP-3, MMP-13, and HA, were significantly suppressed compared to baseline. In two parallel, multinational, 2-year, and much larger studies, that is in the knee osteoarthritis structural arthritis (KOSTAR) study, all doses of risedronate failed to improve above placebo signs and symptoms by the Western Ontario and McMaster Osteoarthritis Index (WOMAC) and did not slow radiographic progression.22 Interestingly, in a subanalysis, it was demonstrated that in subjects with accelerated cartilage degradation at baseline (quantitatively assessed by urinary CTX-II), biochemical response after 6 months of risedronate use was associated with a significant reduction in radiological progression compared to subjects with no response in CTX-II (odds ratio 0.57 [95% CI, 0.39–0.85]).23 Recently, another type II collagen degradation marker was developed, that is Helix II, and evaluated in OA,24 and it has been reported to be complementary to CTX-II.25 Recently, however, the molecular specificity of the Helix II test has been questioned,26 and affi nity for other types of collagen, for example fragments of type III collagen, was reported. To compensate for the loss of ECM, the chondrocytes can up-regulate the synthesis of matrix components, including type II collagen, and these molecules can serve as biological markers of anabolic activity in the cartilage. Recently, we described an enzyme-linked immunosorbent assay (ELISA) detecting the N-terminal propeptide

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of type II collagen, PIINP,27 and reported massive suppression of the synthesis of this molecule in rheumatoid arthritis (RA). This suppression of PIINP expression has later been confirmed in OA,28 and also measurements of the splice variant A, that is PIIANP,29 is suppressed in OA. Others, however, fi nd elevated PIIANP to be associated with radiographic progression of OA over 5 years.30 As PIIANP values are not always consistent,28 further analysis is needed to establish PIIANP as an anabolic marker. A broad range of aggrecan fragments have been characterized in human synovial fluid,31 but only a few tests have been evaluated in appropriate clinical settings. A sandwich assay employing monoclonal antibody mAb OA-1 recognizing the 374 ARGSV neoepitopes after capture by an antibody binding to keratin sulfate detected aggrecan fragments in the 40–100 fmol range in human synovial fluid 32; however, the performance of this assay in human serum has not been reported yet. We have previously reported the quantification of aggrecan fragments in human serum using two different immunoassays,33,34 but further evaluation is required to determine the clinical usefulness of these and other aggrecan tests.

Bone Apart from the articular cartilage, which has attracted most attention in the study of OA pathogenesis, an increasing body of evidence suggests that healthy subchondral bone turnover is prerequisite for preservation of the structural integrity of the articular cartilage (for recent reviews, please refer to Refs. 35–37). The proliferative abnormalities observed in the skeletal compartment in OA not only encompass the bony sclerosis underneath the eroded cartilage (subchondral sclerosis) and osteophytes, but also ossification at the ligaments and the joint capsule is observed.37 During the development of OA, the subchondral cortical and trabecular bone architecture and properties are modified by cellular processes involving both osteoclasts and osteoblasts.35 Markers of bone formation include osteocalcin, bone alkaline phosphates, and the propeptides of type I collagen (N-terminal propeptide of type I procollagen (PINP), C-terminal propeptide of type I procollage (PICP)), and degradation markers include primarily various fragments of type I collagen (CTX-I, N-telopeptide of type I collage (NTX-I), C-terminal propeptide of type I procollagen (ICTP)). In a cross-sectional study, Garnero and coworkers detected a 36%, 38%, and 52% reduction in concentrations of osteocalcin, serum CTX-I, and urine CTX-I, respectively,38 in 67 patients with knee OA compared to the same number of matched controls suggesting a general suppression of bone resorption in this disease group. However, several studies have failed to associate bone markers to

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Table 1. Biological Marker Assays for Detection of Tissue Turnover in the Human Joint ID

Target Molecule

Short Description

References

KS/MAb OA-1

Aggrecan

Mab to keratan sulfate and mAb OA-1 to AGase neoepitope ARGSVIL

32

CS846

Aggrecan

Monoclonal antibody αHFPG-846 (IgM) recognizing chondroitin sulfate moieties on aggrecan (manufacturer Ibex, Canada)

342-G2

Aggrecan

Sandwich ELISA using monoclonal antibody AF28 binding to the neoepitope 342FFGVG and monoclonal antibody F78 binding to G1/G2 for detection of MMP-generated aggrecan fragments

3

G1–G2

Aggrecan

Sandwich ELISA using monoclonal antibody F78 binding to G1/G2 both as capture and detector antibody for detection of intact aggrecan and all aggrecan fragments carrying G1 and/or G2

3

Serum CRP

C-reactive protein

C-reactive protein

46

COMP

Cartilage oligomeric protein

Competition ELISA using polyclonal antibodies. However, sandwich ELISA based on two monoclonal antibodies recognizing different antigenic determinants is available (manufacturer: AnaMar Medical, Sweden)

47

PICP

C-terminus propeptide of type I procollagen

Radioimmunoassay (RIA) using polyclonal antibodies raised to fibroblast PINP digested with bacterial collagenase (manufacturer: Orion Diagnostic, Finland)

48

PINP

N-terminus propeptide of type I procollagen

RIA using polyclonal antibodies recognizing PINP (manufacturer: Orion Diagnostic, Finland) Electrochemiluminescence using MAbs to PINP (manufacturer: Roche Diagnostics, GmbH)

CTX-I

Type I collagen

MAb F1103 and F12 to a cathepsin K-derived C-telopeptide neoepitope EKAHD-β-GGR, where D-β-G denotes an isomerized linkage between D and G (manufacturer: IDS, UK)

50

NTX-I

Type I collagen

Enzyme immunoassay (EIA) detecting a fragment of the N-telopeptide of type I collagen (manufacturer: Inverness Medical, Princeton, NJ)

51

ICTP

Type I collagen

RIA detecting a fragment of the C-telopeptide of type I collagen (manufacturer: Orion Diagnostic, Finland)

52

PIINP

N-terminus propeptide of type I procollagen

Monoclonal antibody recognizing the amino acid sequence GPQPAGEQGPRGDR located in the N-terminal propeptide of type I procollagen

53

PIIANP

N-terminus propeptide of type I procollagen, splice variant A

An ELISA using rabbit polyclonal antibodies raised to recombinant exon-2 of the N-terminal propeptide of type I procollagen

54

CPII

C-propeptide of type II collagen

EIA using rabbit polyclonal antibodies binding to the C-propeptides of type II collagen (manufacturer: Ibex, Canada)

45

9A4/5109

Type II collagen

The collagenase-derived neoepitope ………GEGAAGPSGAEGPPGPQG775 containing the C-terminus of the long ¾ fragment. MAb5109 detects the first underlined sequence, MAb 9A4 the second (neoepitope)

20

CTX-II

Type II collagen

MAb F4601 recognizing the C-telopeptide neoepitope EKGPDP (manufacturer: IDS, UK) MAb 2B4 recognizing the C-telopeptide neoepitope EKGPDP

55, 56

uTIINE

Type II collagen

An LC-MS/MS assay using MAb 9A4 (see above) to affinity purify fragments subjected to MS/MS. Detects a collagenase-derived 45-mer containing the C-terminus of the long ¾ fragment

57

Helix II

Type II collagen

A competition ELISA using polyclonal rabbit antibodies recognizing the neoepitope 622ERGETGPP*GTS632, where P* denotes hydroxyproline

24

C2C

Type II collagen fragment

EIA using a monoclonal antibody recognizing the C-terminus of the 3/4 piece of the degraded α1(II) chain (manufacturer: Ibex, Canada)

58

43–45

23, 49

(Continued)



Table 1. (Continued ) ID

Target Molecule

Short Description

References

C1, C2

Type II collagen fragment

EIA using rabbit polyclonal antibodies binding to the C-terminal (COL2–3/4C (short)) neoepitope generated by cleavage of native human type II collagen by collagenases. Cross-reactivity to type I collagen (manufacturer: Ibex, Canada)

59

PIIINP

N-terminus propeptide of type III procollagen

RIA using polyclonal antibodies recognizing PIIINP (manufacturer: Orion Diagnostic, Finland)

60

Glc-Gal-PYD

Glucosyl-galactosyl-pyridinoline

High performance liquid chromatography (HPLC) method for determination of the non-reducible collagen cross-linker glucosyl-galactosyl-pyridinium present in synovium and absent in bone cartilage and other soft tissue

40

Serum HA

Hyaluronic acid

Based on HA-binding protein isolated from bovine cartilage (manufacturer: e.g., Pharmacia, Sweden)

38

YKL-40

Human glycoprotein 39

A RIA using polyclonal antibodies to a glycoprotein of MW 40 kDa A combined monoclonal capture and polyclonal (rabbit) detector sandwich assay is available (manufacturer: Quidel Corporation, San Diego, CA)

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clinical relevant end points (symptoms and function) as well as to structural damage in the cartilage subcompartment.16,39

Synovium The vast majority of biomarker research has been focused on the two other compartments: the bone and the articular cartilage, but recent data suggest that synovial involvement, namely inflammation and proliferation, is a key component of OA.8 The synovium consists of the intima, which is a layer of cells (mostly macrophages and specialized fibroblasts), a superficial microvasculature net, and the subintima, which contains numerous lymphatic vessels draining liquid from the synovial cavity. The ECM of the subintima consists of type I and III collagens,40 which to some extent carry unusual glycosylations at the hydroxylysine residues, and hyaluronan as well as glycoproteins such as fibronectin, laminin, entactin, and tenascin.41 In particular, the urinary concentration of the glycosylated pyridinium cross-linker glucosyl-galactosyl-pyridinoline (GlcGal-PYD) has been investigated in OA as a marker of synovium tissue destruction.40 The cross-link has been reported to be elevated by 18% (P < 0.05) in knee OA and was significantly associated with total WOMAC index.38 Not surprisingly, Glc-Gal-PYD has been reported to be elevated in RA as well.42

Overview of Biochemical Markers of Joint Tissue As is described earlier, the joint contains several compartments each of which has a complex biochemical composition, and therefore the biochemical marker potential of the joint is substantial. Table 1 provides an overview of the biochemical marker repertoire currently available for quantitative assessment of the tissue turnover in the joint.


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FUTURE PERSPECTIVES This review reflects an intensive area of biomarker research and it is expected that new markers and procedures for their better use will become available for application in clinical studies of OA as well as for improved managing of patients with this serious disease. The recent disappointments in late stage OA drug development have renewed the debate on the potential impact of the biomarker repertoire on this process. In particular, it should be acknowledged that current inclusion criteria for OA trials favors the selection of study participants with relatively progressed disease, and furthermore several phase III clinical trials have reported modest structural progression rates in the untreated study population, for example 13% in the 2-year KOSTAR study discussed earlier,22 while the MMP inhibitor PG-11680062 was investigated in a trial with a 0.134 mm reduction in joint space width over 12 months. Obviously, both these important factors, progressed disease stage and modest progression, pose significant challenges for the drug under investigation. However, biomarkers, in particular the biochemical markers, carry the potential for identification at an early stage of individuals with elevated risk of structural disease progression.17,18,23,63 It is anticipated that future biomarker discovery will aim at combining technologies, as it seems unlikely that any single marker will offer sufficient sensitivity and specificity to allow efficient prediction of disease progression as well as rapid detection of clinically relevant response to medical intervention. Recently, Bauer and coworkers, under the Osteoarthritis Biomarkers Network funded by the National Institutes of Health/ National Institute of Arthritis, Musculoskeletal, and Skin Disease (NIH/NIAMS) proposed a classification scheme for biomarkers termed BIPED, an acronym for Burden of Disease, Investigative,

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Prognostic, Efficacy of Intervention, and Diagnostic.64 The objective of the BIPED classification system is to provide specific biomarker defi nitions for improving development capabilities and analysis OA biomarkers and of communicating advances within a common framework. In brief, the five categories are characterized by the following key features: 1. Burden of disease: Burden-of-disease markers assess the severity or extent of disease, for example severity within a single joint and/or number of joints affected. 2. Investigative: An investigative marker with insufficient information to allow inclusion into one of the existing biomarker categories. The investigative category includes markers for which a relationship to various normal and abnormal parameters of cartilage extracellular matrix turnover has not yet been established in human subjects. 3. Prognostic: The key feature of a prognostic marker is the ability to predict the future onset of OA among persons without OA at baseline or the progression of OA among those with the disease. 4. Efficacy of intervention: An efficacy-of-intervention biomarker provides information about the efficacy of treatment among persons with OA or those at high risk for development of OA. 5. Diagnostic: Diagnostic markers are defi ned by the ability to classify individuals as either having or not having a disease. This scheme offers a framework for evaluating the outcome of future biomarker discovery, and it contemplates integration/combination of independent markers as a single marker will not be applicable across all BIPED categories. Hopefully, biomarker discovery will soon provide the analytical tools required for increasing the effectiveness of the drug development process in joint diseases.

AUTHOR DISCLOSURE STATEMENT A.-C.B.-J., B.C.S., C.C., M.A.K., S.H.M., and P.Q. are employees of Nordic Bioscience A/S. REFERENCES 1. Krasnokutsky S, Samuels J, Abramson SB: Osteoarthritis in 2007. Bull NYU Hosp Jt Dis 2007;65(3):222–228. 2. Rousseau JC, Delmas PD: Biological markers in osteoarthritis. Nat Clin Pract Rheumatol 2007;3(6):346–356. 3. Sumer EU, Schaller S, Sondergaard BC, Tanko LB, Qvist P: Application of biomarkers in the clinical development of new drugs for chondroprotection in destructive joint diseases: a review. Biomarkers 2006;11(6):485–506. 4. Abramson SB, Attur M, Yazici Y: Prospects for disease modification in osteoarthritis. Nat Clin Pract Rheumatol 2006;2:304–312. 5. Garnero P: Use of biochemical markers to study and follow patients with osteoarthritis. Curr Rheumatol Rep 2006;8(1):37–44.

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6. Kraus VB: Do biochemical markers have a role in osteoarthritis diagnosis and treatment? Best Pract Res Clin Rheumatol 2006;20(1):69–80. 7. Schaller S, Henriksen K, Hoegh-Andersen P, Sondergaard BC, Sumer EU, Tanko LB, et al.: In vitro, ex vivo, and in vivo methodological approaches for studying therapeutic targets of osteoporosis and degenerative joint diseases: how biomarkers can assist? Assay Drug Dev Technol 2005;3:553–580. 8. Samuels J, Krasnokutsky S, Abramson SB: Osteoarthritis: a tale of three tissues. Bull NYU Hosp Jt Dis 2008;66(3):244–250. 9. Fosang AJ, Stanton H, Little CB, Atley LM: Neoepitopes as biomarkers of cartilage catabolism. Inflamm Res 2003;52(7):277–282. 10. Zhen EY, Brittain IJ, Laska DA, Mitchell PG, Sumer EU, Karsdal MA, et al.: Characterization of metalloprotease cleavage products of human articular cartilage. Arthritis Rheum 2008;58(8):2420–2431. 11. Behrens F, Kraft EL, Oegema TR: Biochemical changes in articular cartilage after joint immobilization by casting or external fixation. J Orthop Res 1989;7:335–343. 12. Bondeson J, Wainwright S, Hughes C, Caterson B: The regulation of the ADAMTS4 and ADAMTS5 aggrecanases in osteoarthritis: a review. Clin Exp Rheumatol 2008;26(1):139–145. 13. Nagase H, Kashiwagi M: Aggrecanases and cartilage matrix degradation Arthritis Res Ther 2003;5(2):94–103. 14. Gendron C, Kashiwagi M, Lim NH, Enghild JJ, Thogersen IB, Hughes C, et al.: Proteolytic activities of human ADAMTS-5: comparative studies with ADAMTS-4. J Biol Chem 2007;282(25):18294–18306. 15. Garnero P, Delmas PD: Biomarkers in osteoarthritis. Curr Opin Rheumatol 2003;15(5):641–646. 16. Mazieres B, Garnero P, Gueguen A, Abbal M, Berdah L, Lequesne M, et al.: Molecular markers of cartilage breakdown and synovitis at baseline as predictors of structural progression of hip osteoarthritis. The ECHODIAH Cohort. Ann Rheum Dis 2006;65(3):354–359. 17. Reijman M, Hazes JM, Bierma-Zeinstra SM, Koes BW, Christgau S, Christiansen C, et al.: A new marker for osteoarthritis: cross-sectional and longitudinal approach. Arthritis Rheum 2004;50(8):2471–2478. 18. Dam EB, Byrjalsen I, Karsdal MA, Qvist P, Christiansen C: Increased urinary excretion of C-telopeptides of type II collagen (CTX-II) predicts cartilage loss over 21 months by MRI. Osteoarthritis Cartilage 2009;17(3):384–389. 19. Hunter DJ, Li J, LaValley M, Bauer DC, Nevitt M, DeGroot J, et al.: Cartilage markers and their association with cartilage loss on magnetic resonance imaging in knee osteoarthritis: the Boston Osteoarthritis Knee Study. Arthritis Res Ther 2007;9(5):R108. 20. Downs JT, Lane CL, Nestor NB, McLellan TJ, Kelly MA, Karam GA, et al.: Analysis of collagenase-cleavage of type II collagen using a neoepitope ELISA. J Immunol Methods 2001;247(1–2):25–34. 21. Manicourt DH, Azria M, Mindeholm L, Thonar EJ, Devogelaer JP: Oral salmon calcitonin reduces Lequesne’s algofunctional index scores and decreases urinary and serum levels of biomarkers of joint metabolism in knee osteoarthritis. Arthritis Rheum 2006;54(10):3205–3211. 22. Bingham CO, III, Buckland-Wright JC, Garnero P, Cohen SB, Dougados M, Adami S, et al.: Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteoarthritis structural arthritis study. Arthritis Rheum 2006;54(11):3494–3507. 23. Garnero P, Aronstein WS, Cohen SB, Conaghan PG, Cline GA, Christiansen C, et al.: Relationships between biochemical markers of bone and cartilage degradation with radiological progression in patients with knee osteoarthritis receiving risedronate: the Knee Osteoarthritis Structural Arthritis randomized clinical trial. Osteoarthritis Cartilage 2008;16(6):660–666.


24. Charni N, Juillet F, Garnero P: Urinary type II collagen helical peptide (HELIX-II) as a new biochemical marker of cartilage degradation in patients with osteoarthritis and rheumatoid arthritis. Arthritis Rheum 2005;52(4):1081–1090. 25. Charni N, Desmarais S, Bay-Jensen A, Delaisse JM, Percival MD, Garnero P: The type II collagen fragments Helix-II and CTX-II reveal distinct enzymatic pathways of cartilage collagen degradation. Osteoarthritis Cartilage 2008;16(10):1183–1191. 26. Eyre DR, Weis MA: The Helix-II epitope: a cautionary tale from a cartilage biomarker based on an invalid collagen sequence. Osteoarthritis Cartilage 2009;17(4):423–426. 27. Olsen AK, Sondergaard BC, Byrjalsen I, Tanko LB, Christiansen C, Muller A, et al.: Anabolic and catabolic function of chondrocyte ex vivo is reflected by the metabolic processing of type II collagen. Osteoarthritis Cartilage 2007;15: 335–342. 28. Nemirovskiy OV, Sunyer T, Aggarwal P, Abrams M, Hellio Le Graverand MP, Mathews WR: Discovery and development of the N-terminal procollagen type II (NPII) biomarker: a tool for measuring collagen type II synthesis. Osteoarthritis Cartilage 2008;16(12):1494–1500. 29. Rousseau J-C, Zhu Y, Miossec P, Vignon E, Sandell LJ, Garnero P, et al.: Serum levels of type IIA procollagen amino terminal propeptide (PIIANP) are decreased in patients with knee osteoarthritis and rheumatoid arthritis. Osteoarthritis Cartilage 2004;12(6):440–447. 30. Sharif M, Kirwan J, Charni N, Sandell LJ, Whittles C, Garnero P: A 5-yr longitudinal study of type IIA collagen synthesis and total type II collagen degradation in patients with knee osteoarthritis—association with disease progression. Rheumatology (Oxford) 2007;46(6):938–943. 31. Struglics A, Larsson S, Pratta MA, Kumar S, Lark MW, Lohmander LS: Human osteoarthritis synovial fluid and joint cartilage contain both aggrecanaseand matrix metalloproteinase-generated aggrecan fragments. Osteoarthritis Cartilage 2006;14(2):101–113. 32. Pratta MA, Su JL, Leesnitzer MA, Struglics A, Larsson S, Lohmander LS, et al.: Development and characterization of a highly specific and sensitive sandwich ELISA for detection of aggrecanase-generated aggrecan fragments. Osteoarthritis Cartilage 2006;14(7):702–713. 33. Sumer EU, Sondergaard BC, Rousseau JC, Delmas PD, Fosang AJ, Karsdal MA, et al.: MMP and non-MMP-mediated release of aggrecan and its fragments from articular cartilage: a comparative study of three different aggrecan and glycosaminoglycan assays. Osteoarthritis Cartilage 2007;15(2):212–221. 34. Rousseau JC, Sumer EU, Hein G, Sondergaard BC, Madsen S, Pedersen C, et al.: Patients with rheumatoid arthritis have an altered circulatory aggrecan profile. BMC Musculoskelet Disord 2008;9(1):74. 35. Goldring SR: Role of bone in osteoarthritis pathogenesis. Med Clin North Am 2009;93(1):25–35, xv. 36. Karsdal MA, Leeming DJ, Dam EB, Henriksen K, Alexandersen P, Pastoureau P, et al.: Should subchondral bone turnover be targeted when treating osteoarthritis? Osteoarthritis Cartilage 2008;16(6):638–646. 37. Felson DT, Neogi T: Osteoarthritis: is it a disease of cartilage or of bone? Arthritis Rheum 2004;50(2):341–344. 38. Garnero P, Piperno M, Gineyts E, Christgau S, Delmas PD, Vignon E: Cross sectional evaluation of biochemical markers of bone, cartilage, and synovial tissue metabolism in patients with knee osteoarthritis: relations with disease activity and joint damage. Ann Rheum Dis 2001;60(6):619–626. 39. Bruyere O, Collette J, Delmas P, Rouillon A, Roux C, Seidel L, et al.: Interest of biochemical markers of bone turnover for long-term prediction of new vertebral fracture in postmenopausal osteoporotic women. Maturitas 2003;44(4):259–265. 40. Gineyts E, Garnero P, Delmas PD: Urinary excretion of glucosyl-galactosyl pyridinoline: a specific biochemical marker of synovium degradation. Rheumatology (Oxford) 2001;40(3):315–323.


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Address correspondence to: Dr. Per Qvist Herlev Hovedgade 207 Herlev 2730 Denmark E-mail: [email protected]

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