Growth Hormone Does Not Stimulate Early Healing in Rat Tendons

Abstract

Growth Hormone stimulates bone growth and fracture repair. It acts mainly by increasing the systemic levels of IGF-1. Local treatment with IGF-1 appears to stimulate tendon healing. We therefore hypothesized that systemic treatment with Growth Hormone would also stimulate tendon healing. Rat Achilles tendons were transected and left to heal. 4 groups were studied. Intramuscular injections of botulinum toxin A (Botox) were used to reduce loading in 2 groups. The animals were randomized to twice daily injections of Growth Hormone (n=2×10) or saline (n=2×10), and killed after 10 days. Healing was assessed by mechanical testing. Muscle paralysis induced by Botox reduced the strength of the healing tendon by two thirds. Growth Hormone increased femoral and tibial length in the unloaded, and femoral and tibial weight in the loaded group. Body weight and muscle weight were increased in both. In contrast, there was no increase in the strength of the healing tendons, regardless of mechanical loading status. An increase in peak force of the loaded healing tendons by more than 5% could be excluded with 95% confidence. In spite of its stimulatory effects on other tissues, Growth Hormone did not appear to stimulate tendon or tendon repair.

Key words

somatropin - tendon repair - tendon injury - biomechanical evaluation

• References

• 1 Abrahamsson SO, Lundborg G, Lohmander LS. Recombinant human insulin-like growth factor-I stimulates in vitro matrix synthesis and cell proliferation in rabbit flexor tendon. J Orthop Res 1991; 9: 495-502
• 2 Andersson T, Eliasson P, Aspenberg P. Tissue memory in healing tendons: short loading episodes stimulate healing. J Appl Physiol 2009; 107: 417-421
• 3 Bak B, Jorgensen PH, Andreassen TT. Dose response of growth hormone on fracture healing in the rat. Acta Orthop Scand 1990; 61: 54-57
• 4 Bak B, Jorgensen PH, Andreassen TT. Increased mechanical strength of healing rat tibial fractures treated with biosynthetic human growth hormone. Bone 1990; 11: 233-239
• 5 Bak B, Jorgensen PH, Andreassen TT. The stimulating effect of growth hormone on fracture healing is dependent on onset and duration of administration. Clin Orthop Relat Res 1991; 295-301
• 6 Berglund ME, Hart DA, Reno C, Wiig M. Growth factor and protease expression during different phases of healing after rabbit deep flexor tendon repair. J Orthop Res 2011; 29: 886-892
• 7 Bring D, Reno C, Renstrom P, Salo P, Hart D, Ackermann P. Prolonged immobilization compromises up-regulation of repair genes after tendon rupture in a rat model. Scand J Med Sci Sports 2010; 20: 411-417
• 8 Carpenter JE, Hipp JA, Gerhart TN, Rudman CG, Hayes WC, Trippel SB. Failure of growth hormone to alter the biomechanics of fracture-healing in a rabbit model. J Bone Joint Surg Am 1992; 74: 359-367
• 9 Chen CH, Cao Y, Wu YF, Bais AJ, Gao JS, Tang JB.. Tendon healing in vivo: gene expression and production of multiple growth factors in early tendon healing period. J Hand Surg Am 2008; 33: 1834-1842
• 10 Dahlgren LA, van der Meulen MC, Bertram JE, Starrak GS, Nixon AJ. Insulin-like growth factor-I improves cellular and molecular aspects of healing in a collagenase-induced model of flexor tendinitis. J Orthop Res 2002; 20: 910-919
• 11 Doessing S, Heinemeier KM, Holm L, Mackey AL, Schjerling P, Rennie M, Smith K, Reitelseder S, Kappelgaard AM, Rasmussen MH, Flyvbjerg A, Kjaer M. Growth hormone stimulates the collagen synthesis in human tendon and skeletal muscle without affecting myofibrillar protein synthesis. J Physiol 2010; 588: 341-351
• 12 Dowling BA, Dart AJ, Hodgson DR, Rose RJ, Walsh WR. The effect of recombinant equine growth hormone on the biomechanical properties of healing superficial digital flexor tendons in horses. Vet Surg 2002; 31: 320-324
• 13 Eliasson P, Andersson T, Aspenberg P. Rat Achilles tendon healing: mechanical loading and gene expression. J Appl Physiol 2009; 107: 399-407
• 14 Harriss DJ, Atkinson G. Update – Ethical Standards in Sport and Exercise Science Research. J Sports Med 2011; 32: 819-821
• 15 Jarvinen MJ, Lehto MU. The effects of early mobilisation and immobilisation on the healing process following muscle injuries. Sports Med 1993; 15: 78-89
• 16 Kang HJ, Kang ES. Ideal concentration of growth factors in rabbit’s flexor tendon culture. Yonsei Med J 1999; 40: 26-29
• 17 Kolbeck S, Bail H, Schmidmaier G, Alquiza M, Raun K, Kappelgard A, Flyvbjerg A, Haas N, Raschke M. Homologous growth hormone accelerates bone healing – a biomechanical and histological study. Bone 2003; 33: 628-637
• 18 Kurtz CA, Loebig TG, Anderson DD, DeMeo PJ, Campbell PG. Insulin-like growth factor I accelerates functional recovery from Achilles tendon injury in a rat model. Am J Sports Med 1999; 27: 363-369
• 19 Kyparos A, Orth MW, Vailas AC, Martinez DA. Growth and maturational changes in dense fibrous connective tissue following 14 days of rhGH supplementation in the dwarf rat. Growth Horm IGF Res 2002; 12: 367-373
• 20 Nielsen RH, Doessing S, Goto K, Holm L, Reitelseder S, Agergaard J, Schjerling P, Flyvberg A, Kjaer M. GH receptor blocker administration and muscle-tendon collagen synthesis in humans. Growth Horm IGF Res 2011; 21: 140-145
• 21 Provenzano PP, Alejandro-Osorio AL, Grorud KW, Martinez DA, Vailas AC, Grindeland RE, Vanderby Jr R. Systemic administration of IGF-I enhances healing in collagenous extracellular matrices: evaluation of loaded and unloaded ligaments. BMC Physiol 2007; 7: 2
• 22 Raschke M, Kolbeck S, Bail H, Schmidmaier G, Flyvbjerg A, Lindner T, Dahne M, Roenne IA, Haas N. Homologous growth hormone accelerates healing of segmental bone defects. Bone 2001; 29: 368-373
• 23 Raschke M, Rasmussen MH, Govender S, Segal D, Suntum M, Christiansen JS. Effects of growth hormone in patients with tibial fracture: a randomised, double-blind, placebo-controlled clinical trial. Eur J Endocrinol 2007; 156: 341-351
• 24 Schmidmaier G, Wildemann B, Heeger J, Gabelein T, Flyvbjerg A, Bail HJ, Raschke M. Improvement of fracture healing by systemic administration of growth hormone and local application of insulin-like growth factor-1 and transforming growth factor-beta1. Bone 2002; 31: 165-172
• 25 Virchenko O, Aspenberg P. How can one platelet injection after tendon injury lead to a stronger tendon after 4 weeks? Interplay between early regeneration and mechanical stimulation. Acta Orthop 2006; 77: 806-812