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Table 1 Biochemical markers of bone and cartilage turnover measurable in serum, urine and synovial fluid

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

Assay

Target molecule

Short description

Evidence of potential usefulness

KS/mAb OA-1

Aggrecan

Cartilage degradation. Sandwich ELISA using mAb to keratan sulfate and mAb OA-1 to AGase neoepitope ARGSVIL [143]. Detection of fragments in human synovial fluid [143]

[143]

CS846

Aggrecan

Cartilage turnover. mAb αHFPG-846 (IgM) recognizing chondroitin sulfate moieties on aggrecan. Manufacturer: Ibex, Canada

[144, 145]

342-G2

Aggrecan

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

[45]

G1-G2

Aggrecan

Cartilage turnover. Sandwich ELISA using mAb 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

[45, 146]

Serum CRP

C-reactive protein

General inflammation. CRP, an acute phase protein, the assay for which is highly sensitive to detect small changes in magnitude of inflammation

[60, 126, 147–149]

COMP

Cartilage oligomeric protein

Cartilage turnover. Competition ELISA using polyclonal antibodies [58]. However, sandwich ELISA based on two monoclonal antibodies recognizing different antigenic determinants is described [150]. Manufacturer: AnaMar Medical, Sweden

[60, 61, 151–155]

PICP

Carboxyl terminus propeptide of type I procollagen

Bone formation. RIA using polyclonal antibodies raised to fibroblast PICP digested with bacterial collagenase [156]. Manufacturer: Orion Diagnostic, Finland

[156]

PINP

Amino terminus propeptide of type I procollagen

Bone formation. RIA using polyclonal antibodies recognizing PINP [157]. Manufacturer: Orion Diagnostic, Finland. Electrochemiluminecense using mAbs to PINP. Manufacturer: Roche Diagnostics, Germany

[158]

CTX-I

Type I collagen

Bone resorption. A sandwich ELISA using mAb F1103 and F12, both binding to a cathepsin K-derived C-telopeptide neoepitope EKAHD-β-GGR, where D-β-G denotes an isomerized linkage between D and G [84]. Manufacturer: IDS, UK. Also available in an automated version (manufacturer: Roche Diagnostics, Germany)

[87–89]

NTX-I

Type I collagen

Bone resorption. EIA detecting a fragment of the N-telopeptide of type I collagen. Manufacturer: Inverness, US

[159]

ICTP

Type I collagen

MMP-mediated type I collagen type degradation. RIA detecting a fragment of the C-telopeptide of type I collagen. Manufacturer: Orion Diagnostic, Finland

[81, 160]

PIINP

Amino terminus propeptide of type II procollagen

Cartilage formation. mAb recognizing the amino acid sequence GPQPAGEQGPRGDR located in the amino-terminal propeptide of type II procollagen [46]

[46]

PIIANP

Amino terminus propeptide of type II procollagen, splice variant A

Cartilage formation. An ELISA using rabbit polyclonal antibodies raised to recombinant exon-2 of the amino-terminal propeptide of type II procollagen

[71]

CPII

C-propeptide of type II collagen

Cartilage formation. EIA using rabbit polyclonal antibodies binding to the C-propeptides of type II collagen, that is, a marker of collagen synthesis. Manufacturer: Ibex, Canada

[161]

9A4/5109

Type II collagen

Cartilage degradation. The collagenase-derived neoepitope GEGAAGPSGAEGPPGPQG775 containing the carboxyl terminus of the long three-quarter fragment. mAb 5109 detects the first underlined sequence, mAb 9A4 the second (neoepitope)

[162]

CTX-II

Type II collagen

Cartilage degradation. Competition ELISA using mAb F4601 recognizing the C-telopeptide neoepitope EKGPDP (manufacturer: IDS, UK) and mAb 2B4 recognizing the C-telopeptide neoepitope EKGPDP

[42, 163]

uTIINE

Type II collagen

Cartilage degradation. An LC-MS/MS assay using mAb 5109 (see above) to affinity purify fragments subjected to MS/MS. Detects a collagenase-derived 45-mer containing the carboxyl terminus of the long three-quarter fragment

[53, 54]

HELIX-II

Type II collagen

Cartilage degradation. A competition ELISA using polyclonal rabbit antibodies recognizing the neoepitope 622ERGETGPP*GTS632, where P* denotes hydroxyproline. However, a recent publication has highlighted unspecificities [164]

[164–166]

C2C

Type II collagen fragment

Cartilage degradation. EIA using a monoclonal antibody recognizing the carboxyl terminus of the three-quarter piece of the degraded alpha1(II) chain. Manufacturer: Ibex, Canada

[167, 168]

C1,C2

Type II collagen fragment

Collagen degradation. EIA using rabbit polyclonal antibodies binding to the carboxy-terminal (COL2-3/4C(short)) neoepitope generated by cleavage of native human type II collagen by collagenases. Cross-reactivity to type I collagen

[169]

PIIINP

Amino terminus propeptide of type III procollagen

Collagen type II formation. RIA using polyclonal antibodies recognizing PIIINP. Manufacturer: Orion Diagnostic, Finland

[170]

Glc-Gal-PYD

Glucosyl-galactosyl-pyridinoline

Synovial inflammation. 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

[171]

Serum HA

Hyaluronic acid

Cartilage turnover. Based on HA binding protein isolated from bovine cartilage. Manufacturer: for example, Pharmacia, Sweden

 

YKL-40

Human glycoprotein 39

Cartilage turnover. RIA using polyclonal antibodies to a 40 kDa glycoprotein. A combined monoclonal capture and polyclonal (rabbit) detector sandwich assay is available. Manufacturer: Quidel Corporation, US

[172]

OC

Osteocalcin

Bone formation. Numerous assays available

 

MMP-3 and MMPs

Varous cell types

Numerous assays available

[173, 174]

DKK1/Sclerostin

Dkk-1

Measurement of Wnt signaling

[175, 176]

TRACP 5a

Macrophages

Inflammation

[111]

TRACP 5b

Osteoclasts

Osteoclast number. mAb to TRAcP 5b, which may be specific for osteoclasts but not their activity

[74, 111, 177, 178]

Cat K

Osteoclasts

Osteoclast number

[110]

  1. CRP, C-reactive protein; EIA, enzyme immunoassay; HA, hemagglutinin; LC, liquid chromatography; mAb, monoclonal antibody; MMP, matrix metalloproteinase; MS/MS, tandem mass spectrometry; RIA, radioimmune assay. Modified and extended from [179].