International Journal of Bone and Rheumatology Research(IJBRR)  /  IJBRR-2470-4520-02-201

Biochemical Markers in Osteoarthritis


Rubén Daniel Arellano Pérez Verttí1*, Jesús Rafael Argüello Astorga2, Morán-Martínez J1, García-Marín AY2, Guzmán DD2, Lizette Sarai Aguilar Muñiz3, Gonzalez-Galarza FF2

1 Orthopedics Professor and Researcher, Medicine School, University of Coahuila, Mexico.
2 Professor and Researcher, Medicine School, University of Coahuila, Genomics Institute of Science and Medicine, Mexico.
3 Post Graduatestudent, Autonomous University of Coahuila, Torreon Coahuila, Mexico.

*Corresponding Author

Rubén Daniel Arellano Pérez Verttí,
Orthopedics Professor and Researcher, Medicine School,
University of Coahuila, Av. Morelos 900 East, cp 27000,
Torreon Coahuila, Mexico.
E-mail: arellanodaniel1969@gmail.com
Article Type: Review Article

Received: April 11, 2015; Accepted: May 05, 2015; Published: May 09, 2015

Citation: Rubén Daniel Arellano Pérez Verttí, et al., (2015) Biochemical Markers in Osteoarthritis. Int J Bone Rheumatol Res, 2(2), 11-17. doi: dx.doi.org/10.19070/2470-4520-150003

Copyright: Rubén Daniel Arellano Pérez Verttí© 2015. This is an open-access article distributed under the terms of the Creative Commons ttribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.



Abstract

Osteoarthritis (OA) is a chronic disease with a long silent period. The hallmarks of osteoarthritis (OA) include cartilage loss that leads to joint destruction and severe impairment of mobility. Involvement of subchondral bone and synovial tissue is well documentated. OA is the most prevalent cause of disability in the aging population of developing countries.The diagnosis is generally based on clinical symptoms and radiographic changes. However, X-ray has a poor sensitivity that does not allow an early detection of OA or the monitoring of joint damage progression.

Another imaging technique is the magnetic resonance imaging (MRI). Although this medical test is more sensitive than plain radiography, it is more expensive and can´t be routinely applied to many patients.

The limitations offered by such tools have cleared the need to identify more specific biological markers, which evaluate quantitative variations in joint remodeling, diagnostic, prognostic and efficacy of intervention.

OA affects cartilage, subchondral bone, and synovium. Thus, molecules derived from these tissues could be considered as candidates for biological markers in OA, as these molecules have a role in metabolic processes in the joints.

Recent data indicates that some markers could be valuable to diagnose, predict OA progression and assess therapeutic response; however, the interpretation of results should be careful because tissue specificity, clearance rates and circadian variations are still under investigation in most of biomarkers.

Although biomarkers could be considered valuable tools, they still have some limitations in clinical practice and it is necessary to develop and validate specific and sensitive biomarkers.



1.Key Words
2.Introduction
3.Biped Classification
4.Biochemical Markers in OA
5.Articular Cartilage Metabolism Biomarkers
    5.1 Biomarkers reflecting collagen type II synthesis activity
    5.2 Biomarkers reflecting collagen Type II degradation
    5.3 Biomarkers related to proteoglicans metabolism
    5.3 Aggrecan
    5.4 Other non-collagenous proteins
    5.5 Synovial metabolism biomarkers
    5.6 Subchondral bone metabolism biomarkers
6.Future Directions
7.Conclusions
8.Acknowledgement
9.References

Key Words

Osteoarthritis, Biomarkers.


Introduction

Osteoarthritis (OA) is the most frequent degenerative joint disease and one of the leading causes of morbidity and economic burden on health resources. It is a slow progressive disease a which alters all tissues of the affected joint with a long asymptomatic period [1].

OA includes progressive degradation of cartilage, menisci, ligaments, synovial inflammation and changes to the subchondral bone.Current diagnosis of osteoarthritis is mainly based on radiographic criteria (eg., joint space width, osteophyte formation, subchondral sclerosis) and clinical symptoms (eg, pain, rigidity and loss of function) [2].

Although plain radiography is considered to be the gold standard, not only to support diagnosis but to estimate the extent of the disease, its poor sensitivity does not allow early detection of joint degradation and the monitoring of potential treatments; additionally, radiography may not show early biochemical changes within joint, as these may occur many years before symptoms become apparent. Unfortunately, when the patient seeks for medical attention,the disease has already progressed in such a way that the treatment options are limited to surgical alternatives (total joint replacement).

Magnetic resonance imaging (MRI) is a more sensitive imaging method but it is still less used than X-rays due to cost and limited availability.

For that reason, as the prevalence of OA is increasing and early detection of OA has become a clinical challenge, biochemical markers for OA have been proposed to be useful tools not only for early diagnosis and prognostic purpose but for drug development, monitoring intervention and for the development of personalized evidence-based action plans [3].

A biomarker has been defined as¨a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes or pharmacologic responses to a therapeutic intervention¨[4].

Biochemical markers can inform about the molecular events underlying the structural joint changes that characterize knee OA. In addition, they can suggest which metabolic processes may be involved in the development of knee pain [5, 6].

There have been several attempts to improve the accuracy on early diagnosis of OA. In some studies, high sensitive C - reactive protein (hsCRP) has been considered as an early biomarker in OA supporting a pathophysiological role of inflammation in the disease process. However, the association of hsCRP with some other entities (eg. obesity) has limited its use as a tool for early diagnosis of OA [7, 8].

In this review, we describe and summarize the current knowledge of biochemical markers related to components of synovial joints (collagen, proteoglycans, and sinovyum and subchondral bone metabolism).


Biped Classification

The Osteoarthritis Biomarkers Network has developed the BIPED scheme to provide a common communication on this field. Burden of disease, investigative, prognostic, efficacy of intervention and diagnostic are the components of this classification scheme [9].

A sixth category has been added recently under the acronym BIPED: ¨safety¨,(BIPEDS) considering that safety is an important issue for more invasive investigations (eg, exposure to drugs, radiation or contrast agents) [3].

Table 1 depicts BIPED classification.



Table 1. Cartilage, bone and synovium biomarkers mainly studied according to BIPED classification.


Biochemical Markers in OA

The study of biochemical markers in OA has recently received attention as alterations involved in the disease include the three main components of the sinovial joint: cartilage, synovium and subchondralbone [10].


Articular Cartilage Metabolism Biomarkers

Articular cartilage is mainly composed ofwater,collagen (most abundantly type II), proteoglycans (aggrecan), glycoproteins and chondrocytes. A balance between catabolic and anabolic processes normally maintains integrity of tissue;such balance allows keeping the mechanical and physiological properties of cartilage.

Articular cartilage is the target tissue in OA and its gradual degradation causes loss of joint function.It´s described that collagen type II disruption is an early event during the cartilage degradation, preceding proteoglycans loss [11].


Biomarkers reflecting collagen type II synthesis activity

During collagen type II synthesis and secretion process, N and C propeptides are released from the procollagen molecules. For that reason, it is rational to measure biomarkers that reflect the balance between synthesis and degradation of type II collagen.

There are two alternative forms of Type II procollagen. The difference between these two molecules is determined by the presence (IIA) or absence (IIB) of a 69 aminoacids sequence in the Npropeptide. Several studies using assays to measure procollagen type II C-terminal propeptide (PIICP) and the IIA form of type II collagen N-propeptide (PIIANP) in synovial fluid and serum, respectively, have detected changes in levels of these two markers in patients with OA [12-16].


Biomarkers reflecting collagen Type II degradation

C-telopeptide of type II collagen (CTX-II) is a biomarker extensively studied which measures concentrations in urine. CTX-II is the result of collagen type II degradation by collagenases at ¾ length of the triple helix. This degradation process results in two fragments: ¼ length and ¾ length. CTX-II assays recognize on the ¼ length a sequence of 6 aminoacids in the C telopeptide of type II collagen. Elevated levels of UCTX-II have been reported in OA, but also in Rheumatoid Arthritis (RA), non- mineralized cartilage lesions, bone marrow lesions and subcondral bone in animal models. Thus,it has been suggested that CTX-II is not a specific marker of articular cartilage degradation, but could also reflect the remodeling of calcified cartilage [17-21].

Two assays detect the 3/4 fragments by its C-terminal neo-end have been described: the Col 2–3/4 assay (short; C1,C2) recognizing both Type I and typeII collagen because of sequence homology, and the Col 2–3/4 assay(long mono; C2C) recognizing specifically Type II collagen [22].

Protein nitration appears as a key phenomenon in OA.At this respect, two immunoassays detected elevated serum levels of a peptide of 9 amino acids (Coll 2–1) or its nitrated form (Coll 2–1 NO2) inpatients with OA and RAand the ratio Coll2–1 NO2/ Coll 2- 1 was significantly higher in RA than in OA subjects [23].

There are some other biomarkers related to collagen metabolism such as type II collagen α chains collagenase neoepitope (α-CTXII) and Glc-Gal-PYD, collagen type II-specific neoepitope (C2M), C-terminal telopeptide of collagen type I (CTX-I, α-CTX-I), Nterminal telopeptide of collagen type I (NTX-I), and amino terminal propeptide of collagen type I (PINP) [24-27].

Table 2 depicts some biomarkers related to articular cartilage degradation and synthesis.



Table 2. Cartilage collagen Type II degradation and synthesis biomarkers.


Biomarkers related to proteoglicans metabolism

From 10 to 20% of wet weight of cartilage matrixare proteoglycans. These molecules play two fundamental roles in this tissue: the compressive function and maintaining the fluid and electrolyte balance in the articular cartilage.

There are two major classes of proteoglycans found in articular cartilage: aggrecans, consisting in large aggregating proteoglycan monomers and small proteoglycans including decorin, biglycan and fibromodulin [28].


Aggrecan

Aggrecan is the major proteoglycan in the articular cartilage. This molecule plays an important role in maintaining the proper functioning of articular cartilage as it provides a hydrated gel structure (via its interaction with hyaluronan and link protein) that endows the cartilage with load-bearing properties [29].

The level of aggrecan synthesis is analyzed with antibodies recognizing the epitope 846 located on the chondroitin sulfatechains, which increases significantly in OA cartilage [30].

The catabolism of aggrecan is a proteolytic process mediated by aggrecanase activity.Aggrecanases cleave the core protein of aggrecan at several sites generating neoepítopes. These neoepítopes can be detected by several assays.

Aggrecanases are members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) gene family and have been designated ADAMTS-4 and ADAMTS-5, respectively [31].

Through different preclinical models of arthritis, it´s been shown that ADAMTS-5 is protease responsible for driving cartilage loss [32-34].

The presence of aggrecan neoepitopes has shown to be associated with the presence of osteoarthritis.In urine, ARGS (Aggrecan Antibody, N-terminal neoepitope) assay showed a significant elevation in patients with OA [35, 36].

Recently Germaschewski and colleagues developed a novel assayto evaluate ARGS neoepitope concentrations in OA patients. In this study, ARGS neoepitope appears not only as promising prognostic/ stratification marker to facilitate patient selection but as an early pharmacodynamic marker for OA therapeutic trials [37].

The core protein of aggrecan has many chondroitin sulfate and keratan sulfate (KS) chains. Several assays used to assess KS levels in serum or sinovial fluid suggest that KS could be a potential marker of cartilage destruction [38].


Other non-collagenous proteins


COMP

COMP (Cartilage Oligomeric Matrix Protein) is a noncollagenous protein present in cartilage.It is a 524-kDahomopentameric, extracellular matrix glycoprotein member of the thrombospondin family of calcium binding proteins [39].

Although function of COMP remains unclear, it may have a role in endochondral ossification, interacting with collagen fibrils via each C-terminal globule, for extracelular matrix stabilization, influencing fibril formation for collagens type I and II accelerating fibrillogenesis and binding to aggrecan, mediating the organizationof cartilage matrix for its load bearing function [40, 41].

It is important to highlight that COMP levels increase with age, with the number of affected joints, are higher in men than in women and differ among ethnicities [42].

In different studies, high level of COMP was detected in all fluids, but was ten times higher in synovial fluid than in serum indicating preferential release from the affected joints [43].

COMP has shown to be a diagnostic and prognostic biomarker of arthritis, to correlate with the disease severity and have the potential to be used for monitoring articular cartilage destruction and response to different therapeutic modalities [42, 44, 45].

Deamidation is a nonenzymatic mechanism of amino acid damage and aging occurring in numerous proteins. An assay developed against a desamined form of COMP (D-COMP) has shown that serum levels were correlated with hip OA suggesting that D-COMP could be the first OA specific biomarker in a specific joint [46].

Finally, Henrotin et al have proposed a specific immunoassay through proteomic approach, showing Fibulin-3 (Fibulin 3-1 and 3-2) as a potential diagnostic biomarker of OA in urine samples [47].


Synovial metabolism biomarkers


Hyaluronic acid (HA)

Hyaluronic acid (HA) is a constituent of cartilage and the synovium. HA is widely distributed throughout many body tissues, and its presence in the serum can be caused by conditions other tan arthritis (e.g. liver disease). Although its increased levels have been described in OA, this relationship has been demonstrated more specifically in rheumatoid arthtritis [48,49].


Urinary Glucosyl-Galactosyl-Pyridinoline

Crosslinking molecules such as pyridinoline (PYD), which involves the C- and Ntelopeptides link collagen molecules together. Glucosyl galactosyl - pyridinoline (Glc-Gal-PYD), a glycosylated analog of free PYD, is present in human synovial tissue but also reflects degradation of synovial tissue. It is absent from bone, cartilage, and other soft tissues. Urinary excretionis elevatedin OA patients; for that reason is considered a significant predictor of pain and physical function [50, 51].

In other study by Jordan et al, Glc-Gal-Pyd, was associated with OA and disease severity at the tibiofemoral and patellofemoral joints in men [52].


Human Cartilage Protein (YKL-40)

Chitinase-3-like protein 1 or human cartilage glycoprotein 39 is a protein known as YKL-40; belongs to family 18 of the mammalian glycosyl hydrolases and weights 40 kDa [53].

Several different cell types in the joint tissue, including macrophages, articular chondrocytes, synoviocites and other tissues like brain, kidney and placenta secrete YKL-40. A subpopulation ofmacrophages expressesYKL-40 mRNA; this is important as these cellsparticipate in inflammatoryand extracellular matrix (ECM) remodellingprocesses in different tissues [54].

Although YKL-40 lacks enzymatic activity and specific receptor is unknown, may be involved in inflammatory processes in arthritis, asthma, COPD, liver fibrosis, and cancer. YKL-40 binds to important components in cartilage extracellular matrix, which is, proteoglycans and collagens, and influence their production and assembly [55, 56].

In vitro, the expression of YKL-40 is increased in redifferentiation of dedifferenetiated chondrocytes and observed with in vitrochondrogenesis, indicating that YKL-40 is a differentiation marker in chondrocytes [57].

Synoviocytes can secrete YKL-40 during various inflammatory reactions; additionally YKL-40 is produced by osteoblasts, and the primary osteocytes present in osteophytes [58, 59].

Although the molecular processes governing the induction and inhibition of YKL-40 are poorly understood, some studies have reported that IL-1β and TGF-β decreased the secretion of YKL- 40 associated with a reduction in YKL- 40 mRNA levels [60, 61].

In neonatal rat chondrocytes the inflammatory cytokines TNF-α and IL-1 potently induced increased levels of YKL-40 mRNA. In a recent study,YKL-40 level were increased by inflammatory cytokines IL-6 and IL- 17, correlating the levels of intra-articular YKL-40 MMP-1 and MMP- 3, suggesting that YKL-40 is a factor associated with inflammatory and catabolic processes in OA joints [62, 63].

Also, YKL-40 is produced in vivo in older and osteoarthritic cartilage and explant cultures with normal tissue produce low levels of this protein.

According to several studies, changes in the biochemical or biomechanical environment, removal of chondrocytes from their native ECM environment and injury to the cartilage matrix stimulate YKL-40 production. In OA, chondrocytes alter their gene expression patterns in response to changes in their surrounding matrix, the mechanical properties of the cartilage, and various growth factors, cytokines and inflammatory mediators, resulting in continued YKL-40 expression [61, 62, 64].

Insynovial membranes from OA patients, YKL-40-positive cells were found and the number of YKL-40-positive cells correlated with the severity of the synovitis [65].

Despite several studies have demonstrated that YKL-40 levels to be higher in OA patients compared to healthy controls with a significant correlation between synovial fluid and serum, the role of YKL-40 in OA has remained unclear. Is it a molecule related to pathogenesis of disease or is it only a biomarker reflecting severity of inflammatory process? [66-68].


Subchondral bone metabolism biomarkers

The relationship between cartilage and subchondral bone in OA has been matter of controversy. In clinical setting, although unconvincing results have been obtained by using existing bone markers to assess OA, [69] some studies have demonstrated that bone turnover is increased and highly associated to OA and bone marrow lesions detected by magnetic resonance imaging and associated to progression of OA [70, 71].

The increased interest in subchondral bone and OA is due to altered metabolism during OA initial phase and progression of disease. During early phase of disease, the trabecular thickness is reduced due to bone resorption with increased production of cathepsin K and MMPs [72, 73].

As the disease progresses, subchondral bone becomes sclerotic with a thickening of the subchondral plate and higher levels of IGF-1 and TGF-β1. Phenotipic changes in osteoblasts from subchondral bone explains bone sclerosisas an increase in material density and not mineral density with abnormal collagen type I fibers [72, 74].

Subchondral bone Type I collagen degradation can be assessed by measurement of pyridinoline cross-links in urine and excretion is significantly elevated in patients with OA [75].

In addition, NTX-I and CTX-I assays to detect epitopes located in the N-terminal and C-terminal cross-linked telopeptides, respectively, of type I collagen can be used to measure high levels in patients with early and progressive OA [76].

In a recent study by Huebner et al, they evaluate joint tissue remodelling using α-C-telopeptide of type I collagen (α-CTX) and urinary C-telopeptide of type II collagen (CTX-II). These markers wereassociated to severity and progression of OA and localized knee bone turnover. They concluded that α-CTX is indicative of dynamic bone turnover and subsequent radiographic progression of disease, suggesting a role as a sensitive and prognostic marker for the subchondral bone remodeling associated to OA and progression of disease [77].


Future Directions

The focus of this review has been on biochemical markers of OA related to components of synovial joints. At present, it remains unclear if biochemical markers demonstrate optimal validity to evaluate OA patients. OA affects one ora group of joints. Therefore, the optimal marker of disease must provide information of the disease in one joint.

Unfortunately, serum and urine biomarkers exhibit large interindividual variations, thus requiring highly sensitive techniques. Synovial fluid markers may be more informative than systemic markers because they relate to structural damage within a joint. Therefore, synovial fluid markers are promising as diagnostic, prognostic tools and to measure efficacy of intervention.

Early diagnosis of OA is necessary to improve patient outcomes after treatment.Thus, a challenge for the future is the need to develop sensitive biomarkers as surrogates to identify the patient with early symptoms and prediction of clinical response.

Although is not in the scope of this review, including imaging studies such as MRI and genetic tools, such as genome wide association studies, combined with chemicalmarkers may provide relevant information to early detection, evaluate risk of disease progression and improve disease prognosis for personalized evidence- based action plans.

Further understanding of the molecular and cellular basis of OA is fundamental to guide and validatethe development of specific markers, which provide new information on the pathogenesis of OA and might lead to the identification of new markers with potential clinical utilityfor specific strategies to diagnosis and measure efficacy of interventions.


Conclusions

In this brief review, we summarize recent progress in chemical markers investigation. We describe a comprehensive approach, which is necessary to understand the complexity and heterogeneity of the disease.

Osteoarthritis is the most common joint disease, with cartilage loss leading to joint destruction and severe functional impairment. The goal of OA research is to search for new diagnostic and therapeutic strategies. This may help to early diagnose, prevent, reduce or stop the progression of the disease.

In many studies, molecular biomarkers of bone, cartilage, and synovium have been associated with OA, mainly in cross sectional studies. Undoubtedly, there is a need to develop alternative methods with a better sensitivity than plain radiography and less expensive than an MRI.

Several markers, (such as COMP, U-CTX II, C2C, coll2-1, coll2- 1NO2, CP II, PIINP, COMP, 846 epitope, HA, Fib3-1 and Fib 3-2,), have been largely studied and proposed to identify patients with OA, at high risk for rapid progression and for monitoring drug efficacy. However, there is still controversy whether these biomarkers can be usedroutinely in clinical practice.

Recent encouraging results have been provided by many preclinical and clinical studies on diagnostic, prognostic and efficacy of intervention, as shown in a recent meta-analysis by Valdes et al [78]. In that study, it was analysed the largest sample with regards to biochemical markers of cartilage degradation (uCTX-II, COMP, C2M) showing that biomarkers can be valuable prognostic tools for progression of knee OA. However, it is important to keep in mind some limitations when biomarkers are analyzed,regarding preanalytical parameters such as diurnal variation, physical activity or diet, clearance rates, and some covariates (age, gender, BMI, concomitant diseases, drugs) that may affect the concentration of a biomarker and hinder itsuse as a valuable tool for evaluation of OA.

Another important issue is that we must to increase our knowledge about metabolism of biomarkers in different fluids. Usually, biomarkers generated within a joint are released into the synovial fluid; the clearance rates and levels in blood or urine depend on synovial vascularity. Additionally, many of these molecules arise throughout the body, one or a group of joints, and not only from the knee or from the hip and elevated levels do not necessarily reflect disease in one or more peripheral joints. Therefore as noted, by Felson, (2014), the optimal marker of disease may be one that provides information on the disease in a joint [79].

Finally, although biomarkers could be valuable to diagnose, predict OA progression and assess therapeutic response, they have still limitations in clinical practice and it is necessary to develop and validate more specific and sensitive biomarkers.


Acknowledgement

Authors acknowledge Juanita Oropeza for her support in typing this manuscript.


References

  1. Kraus VB, M. Nevitt, L J. Sandell (2010) Summary of the OA biomarkers workshop 2009--biochemical biomarkers: biology, validation, and clinical studies. Osteoarthritis Cartilage 18(6): 742-5.
  2. Bijlsma JW, F. Berenbaum, FP. Lafeber (2011) Osteoarthritis: an update with relevance for clinical practice. Lancet 377(9783): 2115-26.
  3. Kraus VB, Burnett B, Coindreau J, Cottrell S, Eyre D, et al. (2011) Application of biomarkers in the development of drugs intended for the treatment of osteoarthritis. Osteoarthritis Cartilage 19(5): 515-42.
  4. (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69(3): 89-95.
  5. Ishijima M, Watari T, Naito K, Kaneko H, Futami I, et al. (2011) 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 13(1).
  6. Inoue R, Ishibashi Y, Tsuda E, Yamamoto Y, Matsuzaka M, et al. (2011) Knee osteoarthritis, knee joint pain and aging in relation to increasing serum hyaluronan level in the Japanese population. Osteoarthritis Cartilage 19(1): 51-7.
  7. Saxne T, Lindell M, Månsson B, Petersson IF, Heinegård D (2003) Inflammation is a feature of the disease process in early knee joint osteoarthritis: Rheumatology (Oxford) 42(7): 903-4.
  8. Sowers M, Jannausch M, Stein E, Jamadar D, Hochberg M, et al. (2002) C-reactive protein as a biomarker of emergent osteoarthritis. Osteoarthritis Cartilage 10(8): 595-601.
  9. Bauer DC, Hunter DJ, Abramson SB, Attur M, Corr M, Felson D, et al. (2006) Classification of osteoarthritis biomarkers: a proposed approach. Osteoarthritis Cartilage 14(8): 723-7.
  10. Samuels J, S. Krasnokutsky, S.B. Abramson (2008) Osteoarthritis: a tale of three tissues. Bull NYU Hosp Jt Dis 66(3): 244-50.
  11. Huebner JL, Williams JM, Deberg M, Henrotin Y, Kraus VB (2010) Collagen fibril disruption occurs early in primary guinea pig knee osteoarthritis. Osteoarthritis Cartilage 18(3): 397-405.
  12. Shinmei M, Ito K, Matsuyama S, Yoshihara Y, Matsuzawa K (1993) Joint fluid carboxy-terminal type II procollagen peptide as a marker of cartilage collagen biosynthesis. Osteoarthritis and Cartilage 1(2): 121-128.
  13. Nelson F, Dahlberg L, Laverty S, Reiner A, Pidoux I, et al. (1998) Evidence for altered synthesis of type II collagen in patients with osteoarthritis. J Clin Invest 102(12): 2115-25.
  14. Rousseau JC, Zhu Y, Miossec P, Vignon E, Sandell L J, et al. (2004) Serum levels of type IIA procollagen amino terminal propeptide (PIIANP) are decreased in patients with knee osteoarthritis and rheumatoid arthritis. Osteoarthritis Cartilage 12(6): 440-7.
  15. Garnero P, Ayral X, Rousseau JC, Christgau S, Sandell L J, et al. (2002) Uncoupling of type II collagen synthesis and degradation predicts progression of joint damage in patients with knee osteoarthritis. Arthritis Rheum 46(10): 2613-24.
  16. Sharif M, Kirwan J, Charni N, Sandell LJ, Whittles C, et al. (2007) 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 46(6): 938-43.
  17. Bay-Jensen AC, Tabassi NC, Sondergaard LV, Andersen TL, Dagnaes- Hansen F, et al. (2009) The response to oestrogen deprivation of the cartilage collagen degradation marker, CTX-II, is unique compared with other markers of collagen turnover. Arthritis Res Ther 11(1).
  18. Oestergaard S, Sondergaard BC, Hoegh-Andersen P, Henriksen K, Qvist P, et al. (2006) Effects of ovariectomy and estrogen therapy on type II collagen degradation and structural integrity of articular cartilage in rats: implications of the time of initiation. Arthritis Rheum 54(8): 2441-51.
  19. Meulenbelt I, Kloppenburg M, Kroon HM, Houwing-Duistermaat JJ, Garnero P, et al. (2006) Urinary CTX-II levels are associated with radiographic subtypes of osteoarthritis in hip, knee, hand, and facet joints in subject with familial osteoarthritis at multiple sites: the GARP study. Ann Rheum Dis 65(3): 360-5.
  20. Garnero P, Peterfy C, Zaim S, Schoenharting M (2005) Bone marrow abnormalities on magnetic resonance imaging are associated with type II collagen degradation in knee osteoarthritis: a three-month longitudinal study. Arthritis Rheum 52(9): 2822-9.
  21. Christgau S, Garnero P, Fledelius C, Moniz C, Ensig M, et al. (2001) Collagen type II C-telopeptide fragments as an index of cartilage degradation. Bone 29(3): 209-15.
  22. Elsaid K.A, C.O Chichester (2006) Review: Collagen markers in early arthritic diseases. Clin Chim Acta 365(1-2): 68-77.
  23. Abramson S.B (2008) Osteoarthritis and nitric oxide. Osteoarthritis Cartilage 16(2): 60008-4.
  24. Huebner J.L, Jensen A.B, Leeming D. J, Coleman R. E, McDaniel G, et al. (2010) 048 URINARYMARKERS, ALPHA CTX AND CTXII, ARE INDICATIVE OF OA SEVERITY AND BONE TURNOVER. Osteoarthritis and Cartilage 18: S29-S30.
  25. Bay-Jensen AC1, Liu Q, Byrjalsen I, Li Y, Wang J, Pedersen C, Leeming DJ, et al. (2011) Enzyme-linked immunosorbent assay (ELISAs) for metalloproteinase derived type II collagen neoepitope, CIIM--increased serum CIIM in subjects with severe radiographic osteoarthritis. Clin Biochem 44(5-6): 423-9.
  26. Deberg M, Labasse A, Christgau S, Cloos P, Bang Henriksen D, et al. (2005) 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 13(3):258-65.
  27. Deberg MA, Labasse AH, Collette J, Seidel L, Reginster JY, et al. (2005) 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 13(12): 1059-65.
  28. Bhosale A.M, J.B. Richardson (2008) Articular cartilage: structure, injuries and review of management. Br Med Bull 87: 77-95.
  29. Kiani C, Liwen C. H. E. N, WU Y. J, Albert J. Y, Burton B.Y (2002) Structure and function of aggrecan. Cell Res 12(1): 19-32.
  30. Poole AR, Ionescu M, Swan A, Dieppe PA (1994) Changes in cartilage metabolism in arthritis are reflected by altered serum and synovial fluid levels of the cartilage proteoglycan aggrecan. Implications for pathogenesis. J Clin Invest 94(1): 25-33.
  31. Tang, B.L (2001) ADAMTS: a novel family of extracellular matrix proteases. Int J Biochem Cell Biol 33(1): 33-44.
  32. Glasson SS, Askew R, Sheppard B, Carito B, Blanchet T, et al. (2005) Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434(7033): 644-8.
  33. Stanton H, Rogerson FM, East CJ, Golub SB, Lawlor KE, et al. (2005) ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature 434(7033): 648-652.
  34. Little CB, Meeker CT, Golub SB, Lawlor KE, Farmer PJ, et al. (2007) Blocking aggrecanase cleavage in the aggrecan interglobular domain abrogates cartilage erosion and promotes cartilage repair. J Clin Invest 117(6): 1627-36.
  35. Dufield DR, Nemirovskiy OV, Jennings MG, Tortorella MD, Malfait AM, et al. (2010) An immunoaffinity liquid chromatography-tandem mass spectrometry assay for detection of endogenous aggrecan fragments in biological fluids: Use as a biomarker for aggrecanase activity and cartilage degradation. Anal Biochem 406(2): 113-23.
  36. Larsson S, Englund M, Struglics A, Lohmander LS (2010) Association between synovial fluid levels of aggrecan ARGS fragments and radiographic progression in knee osteoarthritis. Arthritis Res Ther 12(6): 31.
  37. Germaschewski FM, Matheny CJ, Larkin J, Liu F, Thomas LR, et al. (2014) Quantitation OF ARGS aggrecan fragments in synovial fluid, serum and urine from osteoarthritis patients. Osteoarthritis Cartilage 22(5): 690-7.
  38. Wakitani S, Okabe T, Kawaguchi A, Nawata M, Hashimoto Y (2010) Highly sensitive ELISA for determining serum keratan sulphate levels in the diagnosis of OA. Rheumatology 49(1): 57-62.
  39. Hedbom E, Antonsson P, Hjerpe A, Aeschlimann D, Paulsson M, et al. (1992) Cartilage matrix proteins. An acidic oligomeric protein (COMP) detected only in cartilage. J Biol Chem 267(9): 6132-6.
  40. Halász K, Kassner A, Mörgelin M, Heinegård D (2007) COMP acts as a catalyst in collagen fibrillogenesis. J Biol Chem 282(43): 31166-73.
  41. Chen FH, Herndon ME, Patel N, Hecht JT, Tuan RS, et al.(2007) Interaction of cartilage oligomeric matrix protein/thrombospondin 5 with aggrecan. J Biol Chem 282(34): 24591-8.
  42. Clark AG, Jordan JM, Vilim V, Renner JB, Dragomir AD, et al. (1999) Serum cartilage oligomeric matrix protein reflects osteoarthritis presence and severity: the Johnston County Osteoarthritis Project. Arthritis Rheum 42(11): 2356-64.
  43. Saxne T, D. Heinegard (1992) Cartilage oligomeric matrix protein: a novel marker of cartilage turnover detectable in synovial fluid and blood. Br J Rheumatol 31(9): 583-91.
  44. Verma P, d K. Dalal (2013) Serum cartilage oligomeric matrix protein (COMP) in knee osteoarthritis: a novel diagnostic and prognostic biomarker. J Orthop Res 31(7): 999-1006.
  45. El-Arman MM, El-Fayoumi G, El-Shal E, El-Boghdady I, El-Ghaweet A (2010) Aggrecan and cartilage oligomeric matrix protein in serum and synovial fluid of patients with knee osteoarthritis. Hss J 6(2): 171-6.
  46. Catterall JB, Hsueh MF, Stabler TV, McCudden CR, Bolognesi M, et al. (2012) Protein modification by deamidation indicates variations in joint extracellular matrix turnover. Journal of Biological Chemistry 287(7): 4640-4651.
  47. Henrotin Y, Gharbi M, Mazzucchelli G, Dubuc JE, De Pauw E, et al. (2012) Fibulin 3 peptides Fib3‐1 and Fib3‐2 are potential biomarkers of osteoarthritis. Arthritis & Rheumatism 64(7): 2260-2267.
  48. Elliott AL, Kraus VB, Luta G, Stabler T, Renner JB, et al. (2005) Serum hyaluronan levels and radiographic knee and hip osteoarthritis in African Americans and Caucasians in the Johnston County Osteoarthritis Project. Arthritis Rheum 52(1): 105-11.
  49. Kraus V.B (2006) Do biochemical markers have a role in osteoarthritis diagnosis and treatment? Best Pract Res Clin Rheumatol 20(1): 69-80.
  50. Garnero P, Gineyts E, Christgau S, Finck B, Delmas PD (2002) Association of baseline levels of urinary glucosyl-galactosyl-pyridinoline and type II collagen C-telopeptide with progression of joint destruction in patients with early rheumatoid arthritis. Arthritis Rheum 46(1): 21-30.
  51. Gineyts E, P. Garnero, P. Delmas (2001) Urinary excretion of glucosyl‐galactosyl pyridinoline: a specific biochemical marker of synovium degradation. Rheumatology 40(3): 315-323.
  52. Jordan KM, Syddall HE, Garnero P, Gineyts E, Dennison EM, et al. (2006) Urinary CTX-II and glucosyl-galactosyl-pyridinoline are associated with the presence and severity of radiographic knee osteoarthritis in men. Annals of the rheumatic diseases 65(7): 871-877.
  53. Huang K, L.D Wu (2009) YKL-40: a potential biomarker for osteoarthritis. J Int Med Res 37(1): p. 18-24.
  54. Volck B1, Johansen JS, Stoltenberg M, Garbarsch C, Price PA, et al. (2001) Studies on YKL-40 in knee joints of patients with rheumatoid arthritis and osteoarthritis. Involvement of YKL-40 in the joint pathology. Osteoarthritis Cartilage 9(3): 203-14.
  55. Lee CG, Da Silva CA, Dela Cruz CS, Ahangari F, Ma B, et al. (2011) Role of chitin and chitinase/chitinase-like proteins in inflammation, tissue remodeling, and injury. Annu Rev Physiol 73: 479-501.
  56. Shao R, Hamel K, Petersen L, Cao QJ, Arenas RB, et al. (2009) YKL-40, a secreted glycoprotein, promotes tumor angiogenesis. Oncogene 28(50):4456-68.
  57. Imabayashi H, Mori T, Gojo S, Kiyono T, Sugiyama T, et al. (2003) Redifferentiation of dedifferentiated chondrocytes and chondrogenesis of human bone marrow stromal cells via chondrosphere formation with expression profiling by large-scale cDNA analysis. Exp Cell Res 288(1): 35-50.
  58. Johansen J.S (2006) Studies on serum YKL-40 as a biomarker in diseases with inflammation, tissue remodelling, fibroses and cancer. Dan Med Bull 53(2): 172-209.
  59. Connor JR, Dodds RA, Emery JG, Kirkpatrick RB, Rosenberg M, et al. (2000) Human cartilage glycoprotein 39 (HC gp-39) mRNA expression in adult and fetal chondrocytes, osteoblasts and osteocytes by in-situ hybridization. Osteoarthritis Cartilage 8(2): 87-95.
  60. De Ceuninck F, Pastoureau P, Bouet F, Bonnet J, Vanhoutte PM (1998) Purification of guinea pig YKL40 and modulation of its secretion by cultured articular chondrocytes. J Cell Biochem 69(4): 414-24.
  61. Johansen JS, Olee T, Price PA, Hashimoto S, Ochs RL, et al. (2001) Regulation of YKL-40 production by human articular chondrocytes. Arthritis Rheum 44(4): 826-37.
  62. Recklies AD, Ling H, White C, Bernier SM (2005) Inflammatory cytokines induce production of CHI3L1 by articular chondrocytes. Journal of Biological Chemistry 280(50): 41213-41221.
  63. Väänänen T, Koskinen A1, Paukkeri EL1, Hämäläinen M1, Moilanen T, et al. (2014) YKL-40 as a novel factor associated with inflammation and catabolic mechanisms in osteoarthritic joints. Mediators Inflamm 215140(10):15.
  64. Volck B, Ostergaard K, Johansen JS, Garbarsch C, Price PA (1999)The distribution of YKL-40 in osteoarthritic and normal human articular cartilage. Scandinavian journal of rheumatology 28(3): 171-179.
  65. Kawasaki M, Hasegawa Y, Kondo S, Iwata H (2001) Concentration and localization of YKL-40 in hip joint diseases. The Journal of rheumatology 28(2): 341-345.
  66. Volck B, Johansen JS, Stoltenberg M, Garbarsch C, Price PA, et al. (2001) Studies on YKL-40 in knee joints of patients with rheumatoid arthritis and osteoarthritis. Involvement of YKL-40 in the joint pathology. Osteoarthritis and Cartilage 9(3): 203-214.
  67. Johansen JS, Hvolris J, Hansen M, Backer V, Lorenzen I, et al. (1996) Serum YKL-40 levels in healthy children and adults. Comparison with serum and synovial fluid levels of YKL-40 in patients with osteoarthritis or trauma of the knee joint. Br J Rheumatol 35(6): 553-9.
  68. Huang K, L Wu (2009) YKL-40: a potential biomarker for osteoarthritis. Journal of International Medical Research 37(1): 18-24.
  69. Hunter DJ, TD Spector (2003) The role of bone metabolism in osteoarthritis. Current rheumatology reports 5(1): 15-19.
  70. Bailey AJ, Mansell JP, Sims TJ, Banse X (2004) Biochemical and mechanical properties of subchondral bone in osteoarthritis. Biorheology 41(3): 349-358.
  71. Garnero P, Peterfy C, Zaim S, Schoenharting M (2005) Bone marrow abnormalities on magnetic resonance imaging are associated with type II collagen degradation in knee osteoarthritis: a three‐month longitudinal study. Arthritis & Rheumatism 52(9): 2822-2829.
  72. Kwan Tat S, Lajeunesse D, Pelletier JP, Martel-Pelletier J (2010) Targeting subchondral bone for treating osteoarthritis: what is the evidence? Best Practice & Research Clinical Rheumatology 24(1): 51-70.
  73. Hayami T, Pickarski M, Zhuo Y, Wesolowski GA, Rodan GA, et al. (2006) Characterization of articular cartilage and subchondral bone changes in the rat anterior cruciate ligament transection and meniscectomized models of osteoarthritis. Bone 38(2): 234-243.
  74. Bailey AJ, TJ Sims, L. Knott (2002) Phenotypic expression of osteoblast collagen in osteoarthritic bone: production of type I homotrimer. The international journal of biochemistry & cell biology 34(2): 176-182.
  75. Stewart A, Black A, Robins S P, Reid DM (1999) Bone density and bone turnover in patients with osteoarthritis and osteoporosis. The Journal of rheumatology 26(3): 622-626.
  76. Bettica P, Cline G, Hart DJ, Meyer J, Spector TD (2002) Evidence for increased bone resorption in patients with progressive knee osteoarthritis: longitudinal results from the Chingford study. Arthritis & Rheumatism 46(12): 3178-3184.
  77. Huebner JL1, Bay-Jensen AC, Huffman KM, He Y, Leeming DJ, et al. (2014) Alpha C‐Telopeptide of Type I Collagen Is Associated With Subchondral Bone Turnover and Predicts Progression of Joint Space Narrowing and Osteophytes in Osteoarthritis. Arthritis & Rheumatology 66(9): 2440- 2449.
  78. Valdes AM, Meulenbelt I, Chassaing E, Arden NK, Bierma-Zeinstra S, et al. (2014) Large scale meta-analysis of urinary C-terminal telopeptide, serum cartilage oligomeric protein and matrix metalloprotease degraded type II collagen and their role in prevalence, incidence and progression of osteoarthritis. Osteoarthritis Cartilage 22(5): 683-9.
  79. Felson DT (2014) The current and future status of biomarkers in osteoarthritis: J Rheumatol 41(5):834-6.

         Indexed in

pubhub  CGS  indexcoop  
j-gate  DOAJ  Google_Scholar_logo

       Total Visitors

SciDoc Counter

Get in Touch

SciDoc Publishers
16192 Coastal Highway
Lewes, Delaware 19958
Tel :+1-(302)-703-1005
Fax :+1-(302)-351-7355
Email: contact.scidoc@scidoc.org


porn