Abstract
Purpose
We evaluated whether synovial fluid (SF) leptin concentrations correlate with pain severity in patients with hip or knee endstage osteoarthritis (OA) and whether they mediate the association between increased joint pain and (1) female gender and (2) obesity.
Methods
We conducted a cross-sectional study including patients with primary hip and knee OA undergoing joint replacement between January and December 2010. SF leptin concentrations obtained on the day of surgery were assessed. Main outcome was pain severity measured pre-operatively using WOMAC and VAS pain scales.
Results
A total of 219 patients were included, 123 hip and 96 knee arthroplasties. Mean age was 72 years, 59 % were women. Mean SF leptin levels were 22.9 (±25.6) ng/ml in women and 5.4 (±5.9) ng/ml in men. Levels >19.6 ng/ml (highest quartile) were significantly associated with increased pain on both WOMAC (mean difference −9.6, 95 % CI −15.1 to −4.0) and VAS scale (mean difference 0.8, 95 % CI 0.2–1.3). Associations remained unchanged after adjusting for age, co-morbidities, contra-lateral arthritic joint, OA site, and disability. The associations observed between increased pain and female gender or obesity were substantially reduced after adjusting for SF leptin.
Conclusion
Joint pain is associated with SF leptin concentrations. Increased pre-operative pain observed in women and obese may be related to high intra-articular leptin levels.
Similar content being viewed by others
References
Creamer P (2004) Current perspectives on the clinical presentation of joint pain in human OA. Novartis Found Symp 260:64–74, discussion 74–8, 100–4, 277–9
Dieppe PA, Lohmander LS (2005) Pathogenesis and management of pain in osteoarthritis. Lancet 365(9463):965–973
Hunter DJ (2009) Insights from imaging on the epidemiology and pathophysiology of osteoarthritis. Radiol Clin North Am 47(4):539–551
Wenham CY, Conaghan PG (2009) Imaging the painful osteoarthritic knee joint: what have we learned? Nat Clin Pract Rheumatol 5(3):149–158
Bedson J, Croft PR (2008) The discordance between clinical and radiographic knee osteoarthritis: a systematic search and summary of the literature. BMC Musculoskelet Disord 9:116
Aspden RM, Scheven BA, Hutchison JD (2001) Osteoarthritis as a systemic disorder including stromal cell differentiation and lipid metabolism. Lancet 357(9262):1118–1120
Dumond H, Presle N, Terlain B, Mainard D et al (2003) Evidence for a key role of leptin in osteoarthritis. Arthritis Rheum 48(11):3118–3129
Figenschau Y, Knutsen G, Shahazeydi S, Johansen O et al (2001) Human articular chondrocytes express functional leptin receptors. Biochem Biophys Res Commun 287(1):190–197
Griffin TM, Huebner JL, Kraus VB, Guilak F (2009) Extreme obesity due to impaired leptin signaling in mice does not cause knee osteoarthritis. Arthritis Rheum 60(10):2935–2944
Simopoulou T, Malizos KN, Iliopoulos D, Stefanou N et al (2007) Differential expression of leptin and leptin’s receptor isoform (Ob-Rb) mRNA between advanced and minimally affected osteoarthritic cartilage; effect on cartilage metabolism. Osteoarthr Cartil 15(8):872–883
de Boer TN, van Spil WE, Huisman AM, Polak AA et al (2012) Serum adipokines in osteoarthritis; comparison with controls and relationship with local parameters of synovial inflammation and cartilage damage. Osteoarthr Cartil 20(8):846–853
Vuolteenaho K, Koskinen A, Moilanen T, Moilanen E (2012) Leptin levels are increased and its negative regulators, SOCS-3 and sOb-R are decreased in obese patients with osteoarthritis: a link between obesity and osteoarthritis. Ann Rheum Dis 71:1912–1913
Jacobsen S, Sonne-Holm S (2005) Increased body mass index is a predisposition for treatment by total hip replacement. Int Orthop 29(4):229–234
Christensen R, Astrup A, Bliddal H (2005) Weight loss: the treatment of choice for knee osteoarthritis? A randomized trial. Osteoarthr Cartil 13:20–27
Toda Y, Toda T, Takemura S, Wada T et al (1998) Change in body fat, but not body weight or metabolic correlates of obesity, is related to symptomatic relief of obese patients with knee osteoarthritis after a weight control program. J Rheumatol 25:2181–2186
Miller GD, Nicklas BJ, Loeser RF (2008) Inflammatory biomarkers and physical function in older, obese adults with knee pain and self-reported osteoarthritis after intensive weight-loss therapy. J Am Geriatr Soc 56:644–651
Monzillo LU, Hamdy O, Horton ES, Ledbury S et al (2003) Effect of lifestyle modification on adipokine levels in obese subjects with insulin resistance. Obes Res 11:1048–1054
Sheu WH, Chang TM, Lee WJ, Ou HC et al (2008) Effect of weight loss on proinflammatory state of mononuclear cells in obese women. Obesity (Silver Spring) 16:1033–1038
Presle N, Pottie P, Dumond H, Guillaume C et al (2006) Differential distribution of adipokines between serum and synovial fluid in patients with osteoarthritis. Contribution of joint tissues to their articular production. Osteoarthr Cartil 14:690–695
Greenspan JD, Craft RM, LeResche L, Arendt-Nielsen L et al (2007) Studying sex and gender differences in pain and analgesia: a consensus report. Pain 132(Suppl 1):S26–S45
Creamer P, Lethbridge-Cejku M, Hochberg MC (1999) Determinants of pain severity in knee osteoarthritis: effect of demographic and psychosocial variables using 3 pain measures. J Rheumatol 26:1785–1792
Tonelli SM, Rakel BA, Cooper NA, Angstom WL et al (2011) Women with knee osteoarthritis have more pain and poorer function than men, but similar physical activity prior to total knee replacement. Biol Sex Differ 2:12
Cho HJ, Chang CB, Yoo JH, Kim SJ et al (2010) Gender differences in the correlation between symptom and radiographic severity in patients with knee osteoarthritis. Clin Orthop Relat Res 468:1749–1758
Holtzman J, Saleh K, Kane R (2002) Gender differences in functional status and pain in a Medicare population undergoing elective total hip arthroplasty. Med Care 40:461–470
Katz JN, Wright EA, Guadagnoli E, Liang MH et al (1994) Differences between men and women undergoing major orthopedic surgery for degenerative arthritis. Arthritis Rheum 37:687–694
Lubbeke A, Duc S, Garavaglia G, Finckh A et al (2009) BMI and severity of clinical and radiographic signs of hip osteoarthritis. Obesity (Silver Spring) 17:1414–1419
Bedaiwy MA, Falcone T, Goldberg JM, Sharma RK et al (2006) Peritoneal fluid leptin is associated with chronic pelvic pain but not infertility in endometriosis patients. Hum Reprod 21:788–791
Lim G, Wang S, Zhang Y, Tian Y et al (2009) Spinal leptin contributes to the pathogenesis of neuropathic pain in rodents. J Clin Invest 119:295–304
Maeda T, Kiguchi N, Kobayashi Y, Ikuta T et al (2009) Leptin derived from adipocytes in injured peripheral nerves facilitates development of neuropathic pain via macrophage stimulation. Proc Natl Acad Sci USA 106:13076–13081
Tian Y, Wang S, Ma Y, Lim G et al (2011) Leptin enhances NMDA-induced spinal excitation in rats: a functional link between adipocytokine and neuropathic pain. Pain 152:1263–1271
Gandhi R, Takahashi M, Smith H, Rizek R et al (2010) The synovial fluid adiponectin-leptin ratio predicts pain with knee osteoarthritis. Clin Rheumatol 29:1223–1228
Massengale M, Lu B, Pan JJ, Katz JN et al (2012) Adipokine hormones and hand osteoarthritis: radiographic severity and pain. PLoS One 7(10):e47860
Bellamy N, Buchanan WW, Goldsmith CH, Campbell J et al (1988) Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol 15:1833–1840
Harris WH (1969) Traumatic arthritis of the hip after dislocation and acetabular fractures: treatment by mold arthroplasty. An end-result study using a new method of result evaluation. J Bone Joint Surg Am 51(4):737–755
Insall JN, Dorr LD, Scott RD, Scott WN (1989) Rationale of the Knee Society clinical rating system. Clin Orthop Relat Res 248:13–14
Ware J Jr, Kosinski M, Keller SD (1996) A 12-item short-form health survey: construction of scales and preliminary tests of reliability and validity. Med Care 34:220–233
Charnley J (1979) Numerical grading of clinical results. In: Charnley J (ed) Low friction arthroplasty of the hip: Theory and practice. Springer Verlag, Berlin, pp 20–24
Kellgren JH, Lawrence JS (1957) Radiological assessment of osteo-arthrosis. Ann Rheum Dis 16(4):494–502
Goldring MB (2009) The link between structural damage and pain in a genetic model of osteoarthritis and intervertebral disc degeneration: a joint misadventure. Arthritis Rheum 60(9):2550–2552
Hunter DJ, McDougall JJ, Keefe FJ (2008) The symptoms of osteoarthritis and the genesis of pain. Rheum Dis Clin North Am 34:623–643
Im HJ, Kim JS, Li X, Kotwal N et al (2010) Alteration of sensory neurons and spinal response to an experimental osteoarthritis pain model. Arthritis Rheum 62:2995–3005
Schaible HG, Ebersberger A, Von Banchet GS (2002) Mechanisms of pain in arthritis. Ann NY Acad Sci 966:343–354
Schaible HG, Richter F, Ebersberger A, Boettger MK et al (2009) Joint pain. Exp Brain Res 196:153–162
Bernotiene E, Palmer G, Gabay C (2006) The role of leptin in innate and adaptive immune responses. Arthritis Res Ther 8:217
Otero M, Lago R, Gomez R, Dieguez C et al (2006) Towards a pro-inflammatory and immunomodulatory emerging role of leptin. Rheumatol (Oxford) 45:944–950
Hoff P, Buttgereit F, Burmester GR, Jakstadt M et al (2013) Osteoarthritis synovial fluid activates pro-inflammatory cytokines in primary human chondrocytes. Int Orthop 37(1):145–151
Vuolteenaho K, Koskinen A, Kukkonen M, Nieminen R et al (2009) Leptin enhances synthesis of proinflammatory mediators in human osteoarthritic cartilage-mediator role of NO in leptin-induced PGE2, IL-6, and IL-8 production. Mediat Inflamm 2009:345838
Hochman JR, French MR, Bermingham SL, Hawker GA (2010) The nerve of osteoarthritis pain. Arthritis Care Res (Hoboken) 62:1019–1023
Hochman JR, Gagliese L, Davis AM, Hawker GA (2011) Neuropathic pain symptoms in a community knee OA cohort. Osteoarthr Cartil 19:647–654
Roubos EW, Dahmen M, Kozicz T, Xu L (2012) Leptin and the hypothalamo-pituitary-adrenal stress axis. Gen Comp Endocrinol 177(1):28–36
Dawson J, Fitzpatrick R, Murray D, Carr A (1996) The problem of ‘noise’ in monitoring patient-based outcomes: generic, disease-specific and site-specific instruments for total hip replacement. J Health Serv Res Policy 1:224–231
Hawker GA, Gignac MA, Badley E, French MR et al (2011) A longitudinal study to explain the pain-depression link in older adults with osteoarthritis. Arthritis Care Res (Hoboken) 63:1382–1390
Mallen CD, Peat G, Thomas E, Dunn KM et al (2007) Prognostic factors for musculoskeletal pain in primary care: a systematic review. Br J Gen Pract 57:655–661
Wylde V, Hewlett S, Learmonth ID, Dieppe P (2011) Persistent pain after joint replacement: prevalence, sensory qualities, and postoperative determinants. Pain 152:566–572
Acknowledgment
The authors would like to express their deep appreciation to all the orthopaedic surgeons, the personnel of the operating room and especially to Mme Carole Bandi and Mme Madeleine Vuillet for their efforts in data collection.
Funding
Internal institutional funding was received for this study.
Prof. Pierre Hoffmeyer received institutional financial support from Medacta, Johnson & Johnson, and Zimmer. The funding sources had no role in the collection, analysis, or interpretation of the data, in the preparation of the manuscript, or its submission for publication.
Conflicts of interest
None declared.
Ethics committee approval
The study was approved by the institutional review board of the Geneva University Hospitals and the patients’ informed consent was obtained (N° 09-215; NAC 09-072).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lübbeke, A., Finckh, A., Puskas, G.J. et al. Do synovial leptin levels correlate with pain in end stage arthritis?. International Orthopaedics (SICOT) 37, 2071–2079 (2013). https://doi.org/10.1007/s00264-013-1982-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00264-013-1982-6