1. CYTOKINES in SPORTS MEDICINE:CYTOKINES in SPORTS MEDICINE:
WhenWhen andand HowHow toto UseUse??
TahsinTahsin BeyzadeogluBeyzadeoglu, MD., MD.
Prof. ofProf. of OrthopaedicsOrthopaedics && TraumatologyTraumatology
IstanbulIstanbul, TURKEY, TURKEY
www.www.beyzadeoglubeyzadeoglu.com.com

2. • Turkish Men National Basketball Team
• Fenerbahce Sports Club
• Turkish Football Federation
• Turkish Basketball Federation
• Turkish Sports Federation for the Physically Disabled

3. WhatWhat isis CytokineCytokine??
• Cyto (cell) + Kinos (movement)
• Small signaling molecules for cell signaling
• Communicating cells
• Immunomodulating agents
• Regulators
• Mediators
– Interleukins, Interferons, Hormons?, GFs?

4. WhatWhat isis CytokineCytokine??
• All cells with a nucleus can produce cytokines
• Production at Golgi Apparatus
• Functions like hormones

5. ClassificationClassification ofof CytokinesCytokines
• Complex Terminalogy
• Interleukins (35)
• Interferons
• Function: TNF, GCSF
• Source: Monokine, Lemphokine
• GF: TGF-β, BMP2-15, EGF, PDGF, IGF-1, IGF-2,
NGF, aFGF, bFGF, Neuroleukin, Amfiregulin, HGF,
etc

6. CytokinesCytokines
• Plays important roles in ACUTE or CHRONIC
INFLAMATION as potential agents
• Important part of autoimmunity

7. CytokinesCytokines inin AcuteAcute InflamationInflamation
• Essential for Immune Response
• Just after injury:
• Neutrophils, Naturel Killer Cells, Macrophages, Mastocytes,
Eosinophils; release Cytokines
• Cytokines;
– effects leucocytes and endotels to release reaactive O2 mediators,
nitric oxide, vasoactive amine, kinin, PG, LT

8. CytokinesCytokines inin AcuteAcute InflamationInflamation
• Most effective Cytokine:
• IL-1, TNF-α and IL-6 (acute phase reactants)

9. CytokinesCytokines inin ChronicChronic
InflamationInflamation
• In late phase of chronic inflamation Cytokines
have negative effects
– Apoptosis, Cell death
• Normally there is balance
• But at disorder of environment (cartilage) or
immune response (romatology)
– Cytokines insist on inflamation

10. CytokinesCytokines inin ChronicChronic
InflamationInflamation
• Cytokines sometimes activite T-cells and may
continue inflamation although there is no
antigen or any more injury
– Unutmaz D, Pileri P, Abrignani S, Antigen-independent activation of naive and
memory resting T cells by a cytokine combination. J Exp Med 1994; 180:1159-66

11. BadBad (IL(IL--1)1) vsvs GoodGood (IL(IL--1Ra, IL1Ra, IL--4, IL4, IL--10)10)
CytokinesCytokines
• We may treat degenerative and inflamatuary
diseases by inhibiting bad cytokines
– Dinarello CA, Interleukin-1. Rev Infect Dis 1984; 6: 51–95.

12. ILIL--11
• Main mediator in degenerative process
• Inhibiting IL-1 may help regeneration
– Dinarello CA, Thompson RC. Blocking IL-1: interleukin 1 receptor antagonist in vivo
and in vitro. Immunol Today 1991; 12: 404–10.
– Fernandes J, Tardif G, Martel-Pelletier J, Lascau-Coman V, Dupuis M, Moldovan F et
al. In vivo transfer of interleukin-1 receptor antagonist gene in osteoarthritic rabbit
knee joints: prevention of osteoarthritis progression. Am J Pathol 1999; 154:1159–69.
– Frisbie DD, McIlwraith CW. Evaluation of gene therapy as a treatment for equine
traumatic arthritis and osteoarthritis. Clin Orthop 2000: S273–87.
– Goldring MB. Anticytokine therapy for osteoarthritis. Expert Opin Biol Ther 2001; 1:
817–29.

13. ILIL--1Ra1Ra
• Surface Receptor Antagonist for IL-1 is also a
Cytokine in serum
• Type I Cytokines: IL-4, IL-10, IL-13 also inhibit IL-1

14. ILIL--1Ra1Ra
• Recombinant IL-1Ra (gene transfer) inhibits
experimental Osteoarthritis
– Pelletier JP, Caron JP, Evans C, Robbins PD, Georgescu HI, Jovanovic D et al. In vivo
suppression of early experimental osteoarthritis by interleukin- 1 receptor antagonist
using gene therapy. Arthritis Rheum 1997; 40: 1012–9.
– Caron JP, Fernandes JC, J. M-P, Tardif G, Mineau F, Geng C et al. Chondroprotective
effect of intraarticular injections of interleukin-1 receptor antagonist in experimental
osteoarthritis. Suppression of collagenase-1 expression. Arthritis Rheum 1996; 39: 1535–
44.
– Frisbie DD, Ghivizzani SC, Robbins PD, Evans CH, McIlwraith CW. Treatment of
experimental equine osteoarthritis by in vivo delivery of the equine interleukin-1 receptor
antagonist gene. Gene Ther 2002; 9: 12–20.

15. ORTHOKINEORTHOKINE®
AutologousAutologous ConditionedConditioned SerumSerum
• From the patient’s own blood
• 10 cc per sample (as much needed)
• Blood is incubated (37°C, 8 h) (protein synthesis)
• In CrSO4 beaded syringe
• Centrifuge 10 min at 5000 rpm
• Aspirate ACS
• Keep at -18 till 7 months

17. ORTHOKINEORTHOKINE®
AutologousAutologous ConditionedConditioned SerumSerum
• From the patient’s own blood
• 10 cc per sample (as much needed)
• Blood is incubated (37°C, 8 h) (protein synthesis)
• In CrSO4 beaded syringe
• Centrifuge 10 min at 5000 rpm
• Aspirate ACS
• Keep at -18 till 7 months

18. ILIL--1Ra1Ra againstagainst ILIL--11
• ACS: ILRa X 140 times + IL-4 + IL-10 + GFs
– Meijer H, Reinecke J, Becker C, Tholen G, Wehling P. The production of anti-
inflammatory cytokines in whole blood by physico-chemical induction. Inflamm Res. 2003
Oct;52(10):404-7.

19. ORTHOKINEORTHOKINE® forfor NerveNerve RootRoot
IrritationIrritation
• Good clinical results for back pain
– Wehling P, Cleveland SJ, Heininger K, Schulitz KP, Reinecke J, Evans CH.
Neurophysiologic changes in lumbar nerve root inflammation in the rat after treatment
with cytokine inhibitors. Evidence for a role of interleukin-1. Spine 1996; 21: 931–5.
– Wehling P, Reinecke J, Meijer H. Epidural Injections with Interleukin-l-Receptor-
Antagonist-Protein (IRAP) in Lumbar Radicular Compression: Pathophysiological
Background, Safety and Clinical Results, InternationaHl Society for the Study of the
Lumbar Spine, Brüssel, 1998. International Society for the Study of the Lumbar Spine.

20. ORTHOKINEORTHOKINE® forfor NerveNerve RootRoot
IrritationIrritation
• Better than Cortison for radikular pain
– Becker C, Heidersdorf S, Drewlo S, de Rodriguez SZ, Krämer J, Willburger RE. Efficacy
of epidural perineural injections with autologous conditioned serum for lumbar radicular
compression: an investigator-initiated, prospective, double-blind, reference-controlled
study. Spine (Phila Pa 1976). 2007;32:1803-8.

21. ORTHOKINEORTHOKINE® forfor AchillesAchilles
• Rapid healing of Achilles in 2 experimental
studies
– Heisterbach PE, Todorov A, Flückiger R, Evans CH, Majewski M. Effect of BMP-12,
TGF-β1 and autologous conditioned serum on growth factor expression in Achilles
tendon healing. Knee Surg Sports Traumatol Arthrosc. 2012;20:1907-14.
– Majewski M, Ochsner PE, Liu F, Flückiger R, Evans CH. Accelerated healing of the rat
Achilles tendon in response to autologous conditioned serum. Am J Sports Med.
2009;37:2117-25.

22. ORTHOKINEORTHOKINE® afterafter ACLACL surgerysurgery
• IL-1β increases tunnel widening
• Less widening with Orthokine®
– Darabos N, Hundric-Haspl Z, Haspl M, Markotic A, Darabos A, Moser C. Correlation
between synovial fluid and serum IL-1beta levels after ACL surgery-preliminary report. Int
Orthop. 2009;33(2):413-8.
– Darabos N, Haspl M, Moser C, Darabos A, Bartolek D, Groenemeyer D. Intraarticular
application of autologous conditioned serum (ACS) reduces bone tunnel widening after
ACL reconstructive surgery in a randomized controlled trial. Knee Surg Sports Traumatol
Arthrosc. 2011;19:S1:36-46.

23. ORTHOKINEORTHOKINE® forfor CartilageCartilage
• Comparing to Hyaluronik Asit and Salin
• Significantly better results
– Baltzer AW, Moser C, Jansen SA, Krauspe R. Autologous conditioned serum (Orthokine)
is an effective treatment for knee osteoarthritis. Osteoarthritis Cartilage. 2009;17(2):152-
60.

24. ORTHOKINEORTHOKINE® forfor MuscleMuscle
• Rapid healing with ACS comparing to
Actovegin/Traumeel
• Due to IL-1Ra ile HGF (Hepatocyte Growth
Factor), TGF-β1 (Transforming Growth Factor β1)
and FGF-2'ye (Fibroblast Growth Factor)
– Wright-Carpenter T, Opolon P, Appell HJ, Meijer H, Wehling P, Mir LM. Treatment of
muscle injuries by local administration of autologous conditioned serum: animal
experiments using a muscle contusion model. Int J Sports Med. 2004; 25:582-7.
– Wright-Carpenter T, Klein P, Schäferhoff P, Appell HJ, Mir LM, Wehling P. Treatment of
muscle injuries by local administration of autologous conditioned serum: a pilot study on
sportsmen with muscle strains. Int J Sports Med. 2004;25:588-93.

25. ORTHOKINEORTHOKINE® forfor MuscleMuscle
• Competative inhibition of IL-1α increases
myogenic differentitation
– Harrington MA, Daub R, Song A, Stasek J, Garcia JG. Interleukin 1 alpha mediated
inhibition of myogenic terminal differentiation: increased sensitivity of Ha-ras transformed
cultures. Cell Growth Differ. 1992;3:241-8.

26. IndicationsIndications forfor ORTHOKINEORTHOKINE®
• Tendon and muscle injuries
• Root irritation
• After ACL surgery
• Cartilage injuries
– Wehling P, Moser C, Frisbie D, McIlwraith CW, Kawcak CE, Krauspe R, Reinecke JA.
Autologous conditioned serum in the treatment of orthopedic diseases: the orthokine
therapy. BioDrugs. 2007;21:323-32.

28. MY INDICATONSMY INDICATONS
• Chronic degenrative cartilage lesions of
atheletes that I prefer to manage
conservatively (4-6 injections)
• Acute/Subacute Bone Marrow Edema (1-3
injections)
• Insertonial Tendinopathies that I prefer to
manage conservatively (1-3 injections)
• After ACL surgery (4-6 injections)
• Grade 2-3 muscle injury of professional
athletes? (3 injections)

31. THANK YOUTHANK YOU
Dr. TahsinDr. Tahsin BeyzadeogluBeyzadeoglu
tbeyzadetbeyzade@@superonlinesuperonline.com.com