The molecular regulation of muscle function in knee osteoarthritis is unclear. Elevated muscle atrophy regulation marker expression was associated with reduced muscle strength in knee osteoarthritis. The level of protein expression appears to be different between muscle, knee joint and serum, suggesting that inflammation is regulated differently within these tissues.
Impaired muscle function is common in knee osteoarthritis (OA). Numerous biochemical molecules have been implicated in the development of OA; however, these have only been identified in the joint and serum. We compared the expression of interleukin-15 (IL-15) and Forkhead box protein-O1 (FoxO1) in muscle of patients with knee OA and asymptomatic individuals and examined whether IL-15 was also present in the joint and serum.
Muscle and blood samples were collected from 19 patients with knee OA and 10 age-matched asymptomatic individuals. Synovial fluid and muscle biopsies were collected from the OA group during knee replacement surgery. IL-15 and FoxO1 were measured in the skeletal muscle. IL-15 abundance was also analysed in the serum of both groups and synovial fluid from the OA group. Knee extensor strength was measured and correlated with IL-15 and FoxO1 in the muscle.
FoxO1 protein expression was higher (p = 0.04), whereas IL-15 expression was lower (p = 0.02) in the muscle of the OA group. Strength was also lower in the OA group and was inversely correlated with FoxO1 expression. No correlation was found between IL-15 in the joint, muscle or serum.
Skeletal muscle, particularly the quadriceps, is affected in people with knee OA where elevated FoxO1 protein expression was associated with reduced muscle strength. While IL-15 protein expression in the muscle was lower in the knee OA group, no correlation was found between the expression of IL-15 protein in the muscle, joint and serum, which suggests that inflammation is regulated differently within these tissues.
Australian Clinical Trials Registry (ACTR) number: ACTRN12613000467730 (http://www.anzctr.org.au/TrialSearch.aspx?searchTxt=ACTRN12613000467730&isBasic=True)
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price includes VAT (USA)
Tax calculation will be finalised during checkout.
Goldring MB, Goldring SR (2007) Osteoarthritis. J Cell Physiol 213(3):626–634. doi:10.1002/jcp.21258
Levinger I, Trenerry M, Levinger P, Feller JA, Bartlett JR, Bergman NR, McKenna M, Cameron-Smith D (2011) Increased inflammatory cytokine expression in the vastus lateralis of patients with knee osteoarthritis. Arthritis Rheum 63(3):1343–1348
Levinger P, Caldow MK, Feller JA, Bartlett JR, Bergman NR, McKenna MJ, Cameron-Smith D, Levinger I (2011) Association between skeletal muscle inflammatory markers and walking pattern in people with knee osteoarthritis. Arthritis Care Res 63(12):1715–1721. doi:10.1002/acr.20625
Quinn LS, Haugk KL, Grabstein KH (1995) Interleukin-15: a novel anabolic cytokine for skeletal muscle. Endocrinology 136(8):3669–3672. doi:10.1210/endo.136.8.7628408
Inoue S, Unsinger J, Davis CG, Muenzer JT, Ferguson TA, Chang K, Osborne DF, Clark AT, Coopersmith CM, McDunn JE, Hotchkiss RS (2010) IL-15 prevents apoptosis, reverses innate and adaptive immune dysfunction, and improves survival in sepsis. J Immunol 184(3):1401–1409. doi:10.4049/jimmunol.0902307
Nielsen AR, Mounier R, Plomgaard P, Mortensen OH, Penkowa M, Speerschneider T, Pilegaard H, Pedersen BK (2007) Expression of interleukin-15 in human skeletal muscle effect of exercise and muscle fibre type composition. J Physiol 584(Pt 1):305–312. doi:10.1113/jphysiol.2007.139618
Tamura Y, Watanabe K, Kantani T, Hayashi J, Ishida N, Kaneki M (2011) Upregulation of circulating IL-15 by treadmill running in healthy individuals: is IL-15 an endocrine mediator of the beneficial effects of endurance exercise? Endocr J 58(3):211–215
Nielsen AR, Hojman P, Erikstrup C, Fischer CP, Plomgaard P, Mounier R, Mortensen OH, Broholm C, Taudorf S, Krogh-Madsen R, Lindegaard B, Petersen AM, Gehl J, Pedersen BK (2008) Association between interleukin-15 and obesity: interleukin-15 as a potential regulator of fat mass. J Clin Endocrinol Metab 93(11):4486–4493. doi:10.1210/jc.2007-2561
Pistilli EE, Siu PM, Alway SE (2007) Interleukin-15 responses to aging and unloading-induced skeletal muscle atrophy. Am J Physiol Cell Physiol 292(4):C1298–C1304. doi:10.1152/ajpcell.00496.2006
Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A, Walsh K, Schiaffino S, Lecker SH, Goldberg AL (2004) Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 117(3):399–412
Mammucari C, Milan G, Romanello V, Masiero E, Rudolf R, Del Piccolo P, Burden SJ, Di Lisi R, Sandri C, Zhao J, Goldberg AL, Schiaffino S, Sandri M (2007) FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab 6(6):458–471. doi:10.1016/j.cmet.2007.11.001
Allen DL, Unterman TG (2007) Regulation of myostatin expression and myoblast differentiation by FoxO and SMAD transcription factors. Am J Physiol Cell Physiol 292(1):C188–C199. doi:10.1152/ajpcell.00542.2005
Kamei Y, Miura S, Suzuki M, Kai Y, Mizukami J, Taniguchi T, Mochida K, Hata T, Matsuda J, Aburatani H, Nishino I, Ezaki O (2004) Skeletal muscle FOXO1 (FKHR) transgenic mice have less skeletal muscle mass, down-regulated type I (slow twitch/red muscle) fiber genes, and impaired glycemic control. J Biol Chem 279(39):41114–41123. doi:10.1074/jbc.M400674200
Hawthorne G, Richardson J, Osborne R (1999) The Assessment of Quality of Life (AQoL) instrument: a psychometric measure of health-related quality of life. Qual Life Res 8(3):209–224
Delbaere K, Hauer K, Lord SR (2009) Evaluation of the Incidental and Planned Activity Questionnaire (IPAQ) for older people. Br J Sports Med 44(14):1029–1034
Bellamy N (1989) Pain assessment in osteoarthritis: experience with the WOMAC osteoarthritis index. Semin Arthritis Rheum 18(4 Suppl 2):14–17
Trenerry MK, Carey KA, Ward AC, Cameron-Smith D (2007) STAT3 signaling is activated in human skeletal muscle following acute resistance exercise. J Appl Physiol 102(4):1483–1489. doi:10.1152/japplphysiol.01147.2006
Buford TW, Cooke MB, Shelmadine BD, Hudson GM, Redd LL, Willoughby DS (2011) Differential gene expression of FoxO1, ID1, and ID3 between young and older men and associations with muscle mass and function. Aging Clin Exp Res 23(3):170–174
Akasaki Y, Hasegawa A, Saito M, Asahara H, Iwamoto Y, Lotz MK (2014) Dysregulated FOXO transcription factors in articular cartilage in aging and osteoarthritis. Osteoarthr Cartil 22(1):162–170. doi:10.1016/j.joca.2013.11.004
Zhang X, Gan L, Pan H, Guo S, He X, Olson ST, Mesecar A, Adam S, Unterman TG (2002) Phosphorylation of serine 256 suppresses transactivation by FKHR (FOXO1) by multiple mechanisms. Direct and indirect effects on nuclear/cytoplasmic shuttling and DNA binding. J Biol Chem 277(47):45276–45284. doi:10.1074/jbc.M208063200
Gonzalez-Alvaro I, Ortiz AM, Garcia-Vicuna R, Balsa A, Pascual-Salcedo D, Laffon A (2003) Increased serum levels of interleukin-15 in rheumatoid arthritis with long-term disease. Clin Exp Rheumatol 21(5):639–642
Sun JM, Sun LZ, Liu J, Su BH, Shi L (2013) Serum interleukin-15 levels are associated with severity of pain in patients with knee osteoarthritis. Dis Markers 35(3):203–206. doi:10.1155/2013/176278
Lamana A, Ortiz AM, Alvaro-Gracia JM, Diaz-Sanchez B, Novalbos J, Garcia-Vicuna R, Gonzalez-Alvaro I (2010) Characterization of serum interleukin-15 in healthy volunteers and patients with early arthritis to assess its potential use as a biomarker. Eur Cytokine Netw 21(3):186–194. doi:10.1684/ecn.2010.0203
McInnes IB, al-Mughales J, Field M, Leung BP, Huang FP, Dixon R, Sturrock RD, Wilkinson PC, Liew FY (1996) The role of interleukin-15 in T-cell migration and activation in rheumatoid arthritis. Nat Med 2(2):175–182
Sakkas LI, Scanzello C, Johanson N, Burkholder J, Mitra A, Salgame P, Katsetos CD, Platsoucas CD (1998) T cells and T-cell cytokine transcripts in the synovial membrane in patients with osteoarthritis. Clin Diagn Lab Immunol 5(4):430–437
Scanzello CR, Umoh E, Pessler F, Diaz-Torne C, Miles T, Dicarlo E, Potter HG, Mandl L, Marx R, Rodeo S, Goldring SR, Crow MK (2009) Local cytokine profiles in knee osteoarthritis: elevated synovial fluid interleukin-15 differentiates early from end-stage disease. Osteoarthr Cartil 17(8):1040–1048. doi:10.1016/j.joca.2009.02.011
Associate Professor. I Levinger was supported by a Future Leader Fellowship (ID: 100040) from the National Heart Foundation of Australia. Associate Professor. P Levinger was supported by funding through the Australian Commonwealth Government Collaborative Research Network.
All participants were informed about the study and signed a consent form. The study protocol was approved by the human research ethics committees of Victoria University, La Trobe University and Warringal Private Hospital.
Conflicts of interest
This study was funded by Arthritis Australia Zimmer Grant.
About this article
Cite this article
Levinger, P., Caldow, M.K., Bartlett, J.R. et al. The level of FoxO1 and IL-15 in skeletal muscle, serum and synovial fluid in people with knee osteoarthritis: a case control study. Osteoporos Int 27, 2137–2143 (2016). https://doi.org/10.1007/s00198-015-3473-7