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Copyright ©The Author(s) 2015.
World J Orthop. Jan 18, 2015; 6(1): 95-105
Published online Jan 18, 2015. doi: 10.5312/wjo.v6.i1.95
Table 1 Summary of studies in which cytokines have shown biochemical marker characteristics
Ref.YearCytokinesJointTissueCondition of samplesSamplesControlsAssayFollow-upResults
Sun et al[65]2013IL-15KneeSerumPrimary Knee OA226106ELISAN/AIL-15 Serum OA ↑ Control
IL-15 positively correlated with WOMAC (Pain)
IL-15 not correlated with KL
Shimura et al[45]2013IL-6KneeSerumPostmenopausal females with medial knee OA160N/ACLIAN/ASerum IL-6 = association with pain severity (VAS) in early stage
Serum IL-6 = association with pain severity (JKOM) in early stage
Wang et al[66]2013IL-18KneePlasma, SF and Articular CartilagePrimary Knee OA3315ELISA + Immunofluorescence StainingN/AIL-18 Plasma +SF OA ↑ Controls
IL-18 positive cells AC OA ↑ Controls
↑ KL = ↑ IL-18 Plasma, SF + AC + ↑ IL-18 positive cells
IL-18 Plasma, SF + AC = Positive correlation
Vincent et al[59]2013IL-1β, IL-6, IL-8, IL-12, TNF-α, IL-4, IL-10 + IL-13KneeSFChronic OAAdult (50-64 yr): 14 Elderly (≥ 65 yr): 14N/AMultiplex6 mo↓Pain severity (NRSpain) = ↓IL-1β
↓ IL-1β, IL-6, IL-8 + IL-12 (Baseline – 6 mo) Adults vs Elderly (not significant)
↓ TNF-α (Baseline – 6 mo) in Adults vs Elderly
Rubenhagen et al[42]2012IL-1Ra, IL-6, IL-8, IL-10, IL-17, VEGF, MCP-1, IL-7, IL-13, IL-18 + HGFKneeSFTotal knee replacements or cruciate ligament, cartilage, or meniscal reconstruction surgery82N/AMultiplex + ELISAN/A↑ SF IL-7 = ↑KL
SF VEGF 2 ×↑ KL=3/4 vs KL=0
IL-7 = positive correlation with age
IL-7 2 ×↑ > 60 years old vs < 60 years old
IL-1Ra, IL-6, IL-8, IL-10, IL-17, MCP-1, IL-13, IL-18 + HGF ≠ association with KL
Chadjich- ristos et al[32]2012IL-1β + TNF-αKneeSFOA Established (Medial menlsectomy)255ELISAN/A↑ IL-1β + TNF-α = ↑ Degree of Inflammation
IL-1β + TNF-α↑ in weeks 2 + 4
IL-1β↓ in week 12
TNF-α↓ in weeks 8 + 12
Saetan et al[83]2011IP-10KneePlasma + SFKnee OA4015ELISAN/AOA SF IP10 2.5 ×↓ than plasma
OA SF IP10 3 ×↓ than control plasma
↑KL = ↓Plasma + SF IP-10
Plasma + SF IP10 inversely correlated with KL (SF less so)
Vangsness et al[84]2011IL-1β, IL-6, IL-8, IL-12p70, IFN-γ, IL-2 + IL-5KneeSFPatients underwent an arthroscopy of the knee for a meniscal tear12N/AImmunoassay high-throughput flow cytometryN/A↑ IL-2 + IL-5 = ↑ Disease severity (ICRS)
↑ IL-1β, IL-6, IL-8, IL-12p70 + IFN-γ = ↑ Disease Severity (ICRS) (Borderline significance; P < 0.10)
IL-1β, IL-6, IL-8, IL-12p70, IFN-γ, IL-2 + IL-5 ≠ association with KL
Orita et al[85]2011IL-6, TNF-α + NGFKneeSFAdult patients with knee pain - No previous OA treatment47N/AELISAN/ATNF-α≠ correlation with KL
TNF-α↓ KL (2-4) vs KL (1)
TNF-α = Positive correlation with WOMAC + WOMAC (Pain, stiffness + physical function)
IL-6 = Negative correlation with KL
IL-6 ↓ KL (3 + 4) vs KL (1 + 2)
IL-6 = Negative correlation with WOMAC (Stiffness)
IL-6 ≠ correlation with WOMAC or WOMAC (Pain or physical function)
Kokebie et al[86]2011IL-1, IL-6, IL-8, IL-11, LIF, COMP + osteocalcinKneeSFFulfilled ACR criteria45RA: 22 Donor: 20ELISAN/AIL-8 RA ↑ OA + Donors
IL-11 RA = OA
IL-11 OA ↑ Donors
LIF Donors ↑ OA + RA
LIF OA = RA
SF WBC positive correlation with IL-6 + IL-1
IL-11, IL-8 + LIF no correlation with SF WBC
No biomarkers correlated with KL or disease activity (WOMAC)
Santos et al[87]2011IL-6KneePlasmaKnee OA (ACR)80N/AELISAN/AIL-6 = inverse correlation with muscle resistance + muscle balance (hamstring)
IL-6 ≠ correlation with functionality
Stannus et al[48]2010IL-1 β, IL-6, TNF-α + hs-CRPKneeSerumSelected randomly from the roll of electors172N/ACLIA3 yrIL-6 + TNF-α Serum = association with JSN (medial tibiofemoral)
IL-6 + TNF-α Serum ≠ association with cartilage volume (tibial)
IL-6 Serum predicted ↓ cartilage volume (medial + tibial)
IL-6 + TNF-α associated with ↓ cartilage volume (medial + lateral)
TNF-α associated with JSN
IL-6 serum associated with knee JSN + Knee cartilage loss (older patients)
Stannus et al[44]2010IL-6HipSerumSelected randomly from the roll of electors193N/AELISAN/AIL-6 Male = Female
↑ IL-6 = ↑ JSN (Female)
IL-6 ≠ association with JSN (Male)
Trunk-fat + Total Fat ratios associated with IL-6
IL-6 ≠ association with presence or severity of osteophytes
Scanzello et al[88]2009IL-15, IL-1β, IL-6, TNF-α, IL-2 + IL-21KneeSFEarly: degenerative meniscal tears Adv: Knee replacement surgeryEarly: 19 Adv: 15N/AELISA + Quantitative PCRN/ASF IL-15 ↑ early vs advanced
Expression of IL-15 early = advanced
Synovial membrane IL-1β, IL-6 + TNF-α early = advanced
SF IL-1β, IL-6 + TNF-α early = advanced
Synovial membrane IL-21 + IL-2 ↓ early vs advanced
SF IL-21 + IL-2 early = advanced
Ling et al[64]2009169 proteins including: cytokines, chemokines + GFsHand and KneeSerumRadiographic OA in one or both knees and one or both handsInitial: 21 Classifying: 19Initial: 61 Classifying: 66RCA enhanced antibody-based protein microarrayOA: 10.03 ± 0.31 Controls: 9.88 ± 0.22 (Years)IL-15 predicted OA at Initial X-ray IL-1α, IL-2, IL-15 + 6Ckine OA ≠ Control IL-15 OA ↑ Control (at Initial + Classifying X-rays)
Livshits et al[47]2009CRP, TNF-α + IL-6KneeSerumWhite femalesYear 5: 430 (IL-6: 429) Year 8: 473 Year 15: 322N/ATNF-α: High-sensitivity ELISA IL-6: Ultra-Sensitivity ELISAYear 5, 8 + 15TNF-α≠ association with RKOA
IL-6 = association with RKOA
IL-6 = association with the development of RKOA
Botha- Scheepers et al[57]2007TNF-α, IL-1β, IL-1Ra + IL-10KneeWhole BloodSymptomatic knee OA in at least one knee at baseline86N/AELISA2 yr↑ TNF-α (Highest quartile) 6 ×↑ Risk of JSN progression
↑ IL-10 (Highest quartile) 4 ×↑ Risk of JSN progression
IL-1β + IL-1Ra ≠ Association with risk of JSN progression
↑ IL-10 (ex vivo production with LPS stimulation) = ↑ Knee OA progression
Doss et al[49]2007IL-6Knee + HipSerum + SFEnd-stage OA (Hip or Knee)49 (Knee: 32, Hip: 17)N/AELISA16% OA ↑ IL-6 vs 84% OA (Possible sub-groups)
IL-6 SF = in Knee vs Hip OA, age, sex, stage of disease or course
Riyazi et al[56]2005TNF-α, IL-1β, IL-1Ra, + IL-10Hand, Spine, Hip or KneeWhole BloodOA at multiple sites305137ELISAN/A↑ IL-1β + IL-1Ra + ↓ IL-10 (ex vivo production with LPS stimulation) = ↑ Multiple site OA familial risk
↑ TNF-α (ex vivo production with LPS stimulation) ≠↑ OA risk
Phenninx et al[61]2004IL-6, CRP, TNF-α, IL-6sR, IL-2sR, TNF-sR1, + TNF-sRKneeSerumOver-weight, older (≥60 yr) + knee OA274N/AELISAN/A↑TNF-sR1 and TNF-sR2 = ↑ WOMAC (Physical Function)
↑IL-6 = ↓Walking speed
↑ TNF-sR = ↑ Pain, Stiffness + KL
IL-1 ≠ association with KL or WOMAC (Physical Function)