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J Knee Surg 2011; 24(4): 241-250
DOI: 10.1055/s-0031-1286192
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© Thieme Medical Publishers

Evolving Biomarkers in Osteoarthritis

Debabrata Patra1 , Linda J. Sandell1 , 2
  • 1Department of Orthopaedic Surgery, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, Missouri
  • 2Department of Cell Biology and Physiology, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, Missouri
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Publication History

Publication Date:
04 October 2011 (online)

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ABSTRACT

Osteoarthritis (OA) is one of the most debilitating diseases affecting mankind with severe financial and emotional consequences. The heterogeneity of the human population, lack of complete understanding of the OA disease process, and the slow progressive nature of the disease characterized by prolonged periods of nonsymptomatic, degenerative changes has hampered development of ideal diagnostic and prognostic portfolios. The difficulties associated with early OA diagnosis by exclusively radiographic techniques has propelled a need to identify specific biomarkers for rapid and effective early OA diagnosis, better patient prognosis, and for monitoring the efficacy of pharmacological interventions to the disease process. This review highlights some of the biochemical biomarkers in current use in OA, their applications and limitations. Investigation of single nucleotide polymorphisms as genetic biomarkers and the application of technologies such as lipidomics and metabolomics to OA are generating potentially additional biomarkers that could be helpful for detecting early OA phenomena in humans.

KEYWORDS

Biomarker - osteoarthritis - collagen degradation - early osteoarthritis - single nucleotide polymorphism

REFERENCES

  • 1 Kraus V B. Waiting for action on the osteoarthritis front.  Curr Drug Targets. 2010;  11 (5) 518-520
    CrossrefPubMedGoogle Scholar
  • 2 Kraus V B, Nevitt M, Sandell L J. Summary of the OA biomarkers workshop 2009—biochemical biomarkers: biology, validation, and clinical studies.  Osteoarthritis Cartilage. 2010;  18 (6) 742-745
    CrossrefPubMedGoogle Scholar
  • 3 Kraus V B, Burnett B, Coindreau J OARSI FDA Osteoarthritis Biomarkers Working Group et al. Application of biomarkers in the development of drugs intended for the treatment of osteoarthritis.  Osteoarthritis Cartilage. 2011;  19 (5) 515-542
    CrossrefPubMedGoogle Scholar
  • 4 Sugiyama S, Itokazu M, Suzuki Y, Shimizu K. Procollagen II C propeptide level in the synovial fluid as a predictor of radiographic progression in early knee osteoarthritis.  Ann Rheum Dis. 2003;  62 (1) 27-32
    CrossrefPubMedGoogle Scholar
  • 5 Sandell L J, Morris N, Robbins J R, Goldring M B. Alternatively spliced type II procollagen mRNAs define distinct populations of cells during vertebral development: differential expression of the amino-propeptide.  J Cell Biol. 1991;  114 (6) 1307-1319
    CrossrefPubMedGoogle Scholar
  • 6 Nemirovskiy O V, Sunyer T, Aggarwal P, Abrams M, Hellio Le Graverand M P, Mathews W R. 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
    CrossrefPubMedGoogle Scholar
  • 7 Christgau S, Garnero P, Fledelius C et al.. Collagen type II C-telopeptide fragments as an index of cartilage degradation.  Bone. 2001;  29 (3) 209-215
    CrossrefPubMedGoogle Scholar
  • 8 Freeston J E, Garnero P, Wakefield R J, Hensor E M, Conaghan P G, Emery P. Urinary type II collagen C-terminal peptide is associated with synovitis and predicts structural bone loss in very early inflammatory arthritis.  Ann Rheum Dis. 2011;  70 (2) 331-333
    CrossrefPubMedGoogle Scholar
  • 9 Bay-Jensen A C, Andersen T L, Charni-Ben Tabassi N et al.. Biochemical markers of type II collagen breakdown and synthesis are positioned at specific sites in human osteoarthritic knee cartilage.  Osteoarthritis Cartilage. 2008;  16 (5) 615-623
    CrossrefPubMedGoogle Scholar
  • 10 Kraus V B, Kepler T B, Stabler T, Renner J, Jordan J. First qualification study of serum biomarkers as indicators of total body burden of osteoarthritis.  PLoS ONE. 2010;  5 (3) e9739
    CrossrefPubMedGoogle Scholar
  • 11 Garnero P, Ayral X, Rousseau J C et al.. Uncoupling of type II collagen synthesis and degradation predicts progression of joint damage in patients with knee osteoarthritis.  Arthritis Rheum. 2002;  46 (10) 2613-2624
    CrossrefPubMedGoogle Scholar
  • 12 Manicourt D H, Azria M, Mindeholm L, Thonar E J, Devogelaer J P. 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
    CrossrefPubMedGoogle Scholar
  • 13 Christgau S, Henrotin Y, Tankó L B et al.. Osteoarthritic patients with high cartilage turnover show increased responsiveness to the cartilage protecting effects of glucosamine sulphate.  Clin Exp Rheumatol. 2004;  22 (1) 36-42
    PubMedGoogle Scholar
  • 14 Nemirovskiy O V, Dufield D R, Sunyer T, Aggarwal P, Welsch D J, Mathews W R. Discovery and development of a type II collagen neoepitope (TIINE) biomarker for matrix metalloproteinase activity: from in vitro to in vivo.  Anal Biochem. 2007;  361 (1) 93-101
    CrossrefPubMedGoogle Scholar
  • 15 Deberg M A, Labasse A H, Collette J, Seidel L, Reginster J Y, Henrotin Y E. One-year increase of Coll 2–1, a new marker of type II collagen degradation, in urine is highly predictive of radiological OA progression.  Osteoarthritis Cartilage. 2005;  13 (12) 1059-1065
    CrossrefPubMedGoogle Scholar
  • 16 Deberg M, Labasse A, Christgau S et al.. New serum biochemical markers (Coll 2–1 and Coll 2–1 NO2) for studying oxidative-related type II collagen network degradation in patients with osteoarthritis and rheumatoid arthritis.  Osteoarthritis Cartilage. 2005;  13 (3) 258-265
    CrossrefPubMedGoogle Scholar
  • 17 Sandy J D, Flannery C R, Neame P J, Lohmander L S. The structure of aggrecan fragments in human synovial fluid. Evidence for the involvement in osteoarthritis of a novel proteinase which cleaves the Glu 373-Ala 374 bond of the interglobular domain.  J Clin Invest. 1992;  89 (5) 1512-1516
    CrossrefPubMedGoogle Scholar
  • 18 Swearingen C A, Carpenter J W, Siegel R et al.. Development of a novel clinical biomarker assay to detect and quantify aggrecanase-generated aggrecan fragments in human synovial fluid, serum and urine.  Osteoarthritis Cartilage. 2010;  18 (9) 1150-1158
    CrossrefPubMedGoogle Scholar
  • 19 Duan Y, Hao D, Li M et al.. Increased synovial fluid visfatin is positively linked to cartilage degradation biomarkers in osteoarthritis.  Rheumatol Int. 2011;  January 19 (Epub ahead of print)
    PubMedGoogle Scholar
  • 20 Hao D, Li M, Wu Z, Duan Y, Li D, Qiu G. Synovial fluid level of adiponectin correlated with levels of aggrecan degradation markers in osteoarthritis.  Rheumatol Int. 2010;  May 13 (Epub ahead of print)
    PubMedGoogle Scholar
  • 21 Scuderi G J, Golish S R, Cook F F, Cuellar J M, Bowser R P, Hanna L S. Identification of a novel fibronectin-aggrecan complex in the synovial fluid of knees with painful meniscal injury.  J Bone Joint Surg Am. 2011;  93 (4) 336-340
    CrossrefPubMedGoogle Scholar
  • 22 Mazzuca S A, Poole A R, Brandt K D, Katz B P, Lane K A, Lobanok T. Associations between joint space narrowing and molecular markers of collagen and proteoglycan turnover in patients with knee osteoarthritis.  J Rheumatol. 2006;  33 (6) 1147-1151
    PubMedGoogle Scholar
  • 23 Uebelhart D, Thonar E J, Delmas P D, Chantraine A, Vignon E. Effects of oral chondroitin sulfate on the progression of knee osteoarthritis: a pilot study.  Osteoarthritis Cartilage. 1998;  6 (Suppl A) 39-46
    CrossrefPubMedGoogle Scholar
  • 24 Garnero P, Delmas P D. Noninvasive techniques for assessing skeletal changes in inflammatory arthritis: bone biomarkers.  Curr Opin Rheumatol. 2004;  16 (4) 428-434
    CrossrefPubMedGoogle Scholar
  • 25 Marx R E, Cillo Jr J E, Ulloa J J. Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment.  J Oral Maxillofac Surg. 2007;  65 (12) 2397-2410
    CrossrefPubMedGoogle Scholar
  • 26 Bingham III C O, Buckland-Wright J C, Garnero P 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
    CrossrefPubMedGoogle Scholar
  • 27 Spector T D, Conaghan P G, Buckland-Wright J C et al.. Effect of risedronate on joint structure and symptoms of knee osteoarthritis: results of the BRISK randomized, controlled trial [ISRCTN01928173].  Arthritis Res Ther. 2005;  7 (3) R625-R633
    CrossrefPubMedGoogle Scholar
  • 28 Ishijima M, Watari T, Naito K et al.. Relationships between biomarkers of cartilage, bone, synovial metabolism and knee pain provide insights into the origins of pain in early knee osteoarthritis.  Arthritis Res Ther. 2011;  13 (1) R22
    CrossrefPubMedGoogle Scholar
  • 29 Berry P A, Maciewicz R A, Cicuttini F M, Jones M D, Hellawell C J, Wluka A E. Markers of bone formation and resorption identify subgroups of patients with clinical knee osteoarthritis who have reduced rates of cartilage loss.  J Rheumatol. 2010;  37 (6) 1252-1259
    CrossrefPubMedGoogle Scholar
  • 30 Gineyts E, Garnero P, Delmas P D. Urinary excretion of glucosyl-galactosyl pyridinoline: a specific biochemical marker of synovium degradation.  Rheumatology (Oxford). 2001;  40 (3) 315-323
    CrossrefPubMedGoogle Scholar
  • 31 Jordan K M, Syddall H E, Garnero P et al.. Urinary CTX-II and glucosyl-galactosyl-pyridinoline are associated with the presence and severity of radiographic knee osteoarthritis in men.  Ann Rheum Dis. 2006;  65 (7) 871-877
    PubMedGoogle Scholar
  • 32 Gineyts E, Mo J A, Ko A et al.. Effects of ibuprofen on molecular markers of cartilage and synovium turnover in patients with knee osteoarthritis.  Ann Rheum Dis. 2004;  63 (7) 857-861
    CrossrefPubMedGoogle Scholar
  • 33 Kokebie R, Aggarwal R, Lidder S et al.. The role of synovial fluid markers of catabolism and anabolism in osteoarthritis, rheumatoid arthritis and asymptomatic organ donors.  Arthritis Res Ther. 2011;  13 (2) R50
    CrossrefPubMedGoogle Scholar
  • 34 Andersson M L, Petersson I F, Karlsson K E et al.. Diurnal variation in serum levels of cartilage oligomeric matrix protein in patients with knee osteoarthritis or rheumatoid arthritis.  Ann Rheum Dis. 2006;  65 (11) 1490-1494
    CrossrefPubMedGoogle Scholar
  • 35 Kong S Y, Stabler T V, Criscione L G, Elliott A L, Jordan J M, Kraus V B. Diurnal variation of serum and urine biomarkers in patients with radiographic knee osteoarthritis.  Arthritis Rheum. 2006;  54 (8) 2496-2504
    CrossrefPubMedGoogle Scholar
  • 36 Criscione L G, Elliott A L, Stabler T, Jordan J M, Pieper C F, Kraus V B. Variation of serum hyaluronan with activity in individuals with knee osteoarthritis.  Osteoarthritis Cartilage. 2005;  13 (9) 837-840
    CrossrefPubMedGoogle Scholar
  • 37 Qvist P, Christgau S, Pedersen B J, Schlemmer A, Christiansen C. Circadian variation in the serum concentration of C-terminal telopeptide of type I collagen (serum CTx): effects of gender, age, menopausal status, posture, daylight, serum cortisol, and fasting.  Bone. 2002;  31 (1) 57-61
    CrossrefPubMedGoogle Scholar
  • 38 Ikegawa S. Genetic analysis of skeletal dysplasia: recent advances and perspectives in the post-genome-sequence era.  J Hum Genet. 2006;  51 (7) 581-586
    CrossrefPubMedGoogle Scholar
  • 39 Briggs M D, Hoffman S M, King L M et al.. Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene.  Nat Genet. 1995;  10 (3) 330-336
    CrossrefPubMedGoogle Scholar
  • 40 Czarny-Ratajczak M, Lohiniva J, Rogala P et al.. A mutation in COL9A1 causes multiple epiphyseal dysplasia: further evidence for locus heterogeneity.  Am J Hum Genet. 2001;  69 (5) 969-980
    CrossrefPubMedGoogle Scholar
  • 41 Chapman K L, Mortier G R, Chapman K, Loughlin J, Grant M E, Briggs M D. Mutations in the region encoding the von Willebrand factor A domain of matrilin-3 are associated with multiple epiphyseal dysplasia.  Nat Genet. 2001;  28 (4) 393-396
    CrossrefPubMedGoogle Scholar
  • 42 Tiller G E, Rimoin D L, Murray L W, Cohn D H. Tandem duplication within a type II collagen gene (COL2A1) exon in an individual with spondyloepiphyseal dysplasia.  Proc Natl Acad Sci U S A. 1990;  87 (10) 3889-3893
    CrossrefPubMedGoogle Scholar
  • 43 Miyamoto Y, Mabuchi A, Shi D et al.. A functional polymorphism in the 5′ UTR of GDF5 is associated with susceptibility to osteoarthritis.  Nat Genet. 2007;  39 (4) 529-533
    CrossrefPubMedGoogle Scholar
  • 44 Daans M, Luyten F P, Lories R J. GDF5 deficiency in mice is associated with instability-driven joint damage, gait and subchondral bone changes.  Ann Rheum Dis. 2011;  70 (1) 208-213
    CrossrefPubMedGoogle Scholar
  • 45 Chapman K, Takahashi A, Meulenbelt I et al.. A meta-analysis of European and Asian cohorts reveals a global role of a functional SNP in the 5′ UTR of GDF5 with osteoarthritis susceptibility.  Hum Mol Genet. 2008;  17 (10) 1497-1504
    CrossrefPubMedGoogle Scholar
  • 46 Kizawa H, Kou I, Iida A et al.. An aspartic acid repeat polymorphism in asporin inhibits chondrogenesis and increases susceptibility to osteoarthritis.  Nat Genet. 2005;  37 (2) 138-144
    CrossrefPubMedGoogle Scholar
  • 47 Stern A G, de Carvalho M R, Buck G A I-NODAL Network et al. Association of erosive hand osteoarthritis with a single nucleotide polymorphism on the gene encoding interleukin-1 beta.  Osteoarthritis Cartilage. 2003;  11 (6) 394-402
    CrossrefPubMedGoogle Scholar
  • 48 Vaes R B, Rivadeneira F, Kerkhof J M et al.. Genetic variation in the GDF5 region is associated with osteoarthritis, height, hip axis length and fracture risk: the Rotterdam study.  Ann Rheum Dis. 2009;  68 (11) 1754-1760
    CrossrefPubMedGoogle Scholar
  • 49 Panoutsopoulou K, Southam L, Elliott K S arcOGEN Consortium et al. Insights into the genetic architecture of osteoarthritis from stage 1 of the arcOGEN study.  Ann Rheum Dis. 2011;  70 (5) 864-867
    CrossrefPubMedGoogle Scholar
  • 50 Castro-Perez J M, Kamphorst J, DeGroot J et al.. Comprehensive LC-MS E lipidomic analysis using a shotgun approach and its application to biomarker detection and identification in osteoarthritis patients.  J Proteome Res. 2010;  9 (5) 2377-2389
    CrossrefPubMedGoogle Scholar
  • 51 Zhai G, Wang-Sattler R, Hart D J et al.. Serum branched-chain amino acid to histidine ratio: a novel metabolomic biomarker of knee osteoarthritis.  Ann Rheum Dis. 2010;  69 (6) 1227-1231
    CrossrefPubMedGoogle Scholar

Linda J. SandellPh.D. 

Professor, Department of Cell Biology and Physiology, Washington University School of Medicine at Barnes-Jewish Hospital

660 S. Euclid Avenue, St. Louis, MO 63110

Email: sandelll@wudosis.wustl.edu

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