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Journal of Orthopaedic Science

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01-01-2015 | Original Article

Therapeutic effects of high molecular weight hyaluronan injections for tendinopathy in a rat model

Authors: Mamoru Yoshida, Hiroki Funasaki, Makoto Kubota, Keishi Marumo

Published in: Journal of Orthopaedic Science | Issue 1/2015

Abstract

Background

Tendinopathy is the most common tendon disorder. The etiology is still uncertain, and the disorder poses many therapeutic problems. In a few clinical studies, analgesic effects of high molecular weight hyaluronan (HMW HA) injections were observed, but the underlying mechanisms were not elucidated. In the present study, we analyzed the therapeutic effects of hyaluronan injections for tendinopathy in an animal model.

Methods

We made the tendinopathy rat model using a rodent treadmill machine. Rats with tendinopathy were injected with HMW HA (HA group), normal saline (NS group), or nothing (control group) into the space between the patellar tendon and the fat pad bilaterally, or were injected with HMW HA into the right knees and with saline to the left knees (HA/NS group), 5 times every 4 days. To assess the pain-relieving effect of HA, the spontaneous locomotor activities at night (12 h) and weight bearing of hind paws were measured every day. Histological sections of the patellar tendon stained with hematoxylin–eosin or prepared by TdT-mediated dUTP nick end labeling were microscopically analyzed.

Results

The number of spontaneous locomotor activities in the HA group was significantly larger than those in NS or control groups, and in the HA group they recovered up to a healthy level. The percent weight distribution of the right hind paws was significantly increased along with the number of injections. On histologic examinations, the numbers of microtears, laminations, or apoptotic cells in the patellar tendons in the HA group were significantly lower than those in the NS or the control groups.

Conclusions

The injections of HMW HA were effective for pain relief and for partial restoration of the patellar tendon in our tendinopathy rat model, and thus may become an effective therapeutic modality for the disease.

Yinghua X, George ACM. The basic science of tendinopathy. Clin Orthop Relat Res. 2008;466:1528–38.CrossRef

Higashiyama I, Kumai T, Hayashi K, Shinohara Y, Matsuda T, Tanaka Y, Takakura Y. Effect of hyaluronic acid for plantar fasciitis. J Jpn Soc Surg Foot. 2007;28:25–8.

Petrella RJ, Cogliano A, Decaria J, Mohamed N, Lee R. Management of tennis elbow with sodium hyaluronate periarticular injections. Sports Med Arthrosc Rehabil Ther Technol. 2010;2:4.PubMedCentralPubMedCrossRef

Flatow EL, Nasser P, Lee L, Schaffler MB, Jepsen KJ. Overestimation of the degradation state in fatigue loaded tendon due to transient effects. Trans Orthop Res Soc. 2002;27:621.

Wang VM, Laudier D, Tsai CW, Jepsen KJ, Schaffler MB, Flatow EL. Imaging normal and damaged tendons: development and application of novel tissue processing techniques. Trans Orthop Res Soc. 2005;30:321.

Lee H, Wang VM, Laudier DM, Schaffler MB, Flatow EL. A novel in vivo model of tendon fatigue damage accumulation. Trans Orthop Res Soc. 2006;31:1058.

Masuo Y, Matsumoto Y, Morita S, Noguchi J. A novel method for counting spontaneous motor activity in the rat. Brain Res Protoc. 1997;1:321–6.CrossRef

Hara J, Beuckmann TC, Nambu T, Willie TJ, Chemelli MR, Sinton MC, Sugiyama F, Yagami K, Goto K, Yanagisawa M, Sakurai T. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron. 2001;30:345–54.PubMedCrossRef

Shibakusa T, Iwaki Y, Mizunoya W, Matsumura S, Nishizawa Y, Inoue K, Fushiki T. The physiological and behavioral effects of subchronic intracisternal administration of TGF-β in rats: comparison with the effects of CRF. Biomed Res. 2006;27:297–305.PubMedCrossRef

10.

Watabiki T, Kiso T, Tsukamoto M, Aoki T, Matsuoka N. Intrathecal administration of AS1928370, a transient receptor potential vanilloid 1 antagonist, attenuates mechanical allodynia in a mouse model of neuropathic pain. Biol Pharm Bull. 2011;34:1105–8.PubMedCrossRef

11.

Mihara M, Higo S, Uchiyama Y, Tanabe K, Saito K. Different effects of high molecular weight sodium hyaluronate and NSAID on the progression of the cartilage degeneration in rabbit OA model. Osteoarthr Cartil. 2007;15:543–9.PubMedCrossRef

12.

Ghosh P. The role of hyaluronic acid (hyaluronan) in health and disease: interactions with cells, cartilage and components of the synovial fluid. Clin Exp Rheumatol. 1994;12:75–82.PubMed

13.

Abatangelo G, O’Regan M. Hyaluronan: biological role and function in articular joints. Eur J Rheumatol Inflamm. 1995;15:9–16.

14.

Laurent TC, Laurent UBG, Fraser JRE. The structure of hyaluronan: an overview. Immunol Cell Biol. 1996;74:A1–7.PubMedCrossRef

15.

Kato Y, Nishimura M, Kikuchi T, Sawai T. Accessibility of high molecular weight hyaluronan to articular cartilage and synovium. Clin Rheumatol. 2009;21:20–31.

16.

Maganaris CN, Narici MV, Almekinders NC, Maffulli N. Biomechanics and pathophysiology of overuse tendon injuries. Sports Med. 2004;34:1005–17.PubMedCrossRef

17.

Lisignoli G, Grassi F, Zini N, Toneguzzi S, Piacentini A, Guidolin D, Bevilacqua C, Facchini A. Anti-Fas-induced apoptosis in chondrocytes reduced by hyaluronan: evidence for CD44 and CD54 involvement. Arthritis Rheum. 2001;44:1800–7.PubMedCrossRef

18.

Yamazaki K, Fukuda K, Matsukawa M, Hara F, Matsushita T, Yamamoto N, Yoshida K, Munakata H. Cyclic tensile stretch loaded on bovine chondrocytes causes depolymerization of hyaluronan: involvement of reactive oxygen species. Arthritis Rheum. 2003;48:3151–8.PubMedCrossRef

19.

Yamazaki K, Fukuda K, Matsukawa M, Hara F, Yoshida K, Akagi M, Munakata H, Hamanishi C. Reactive oxygen species depolymerize hyaluronan: involvement of the hydroxyl radical. Pathophysiology. 2003;9:215–20.PubMedCrossRef

20.

Yagishita K, Sekiya I, Sakaguchi Y, Shinomiya K, Muneta T. The effect of hyaluronan on tendon healing in rabbits. Arthroscopy. 2005;21:1330–6.PubMedCrossRef

21.

Mast AB, Diegelmann FR, Krummel MT, Cohen KI. Hyaluronic acid modulates proliferation, collagen and protein synthesis of cultured fetal fibroblasts. Matrix. 1993;13:441–6.PubMedCrossRef

22.

Greco MR, Iocono AJ, Ehrlich PH. Hyaluronic acid stimulates human fibroblast proliferation within a collagen matrix. J Cell Physiol. 1998;177:465–73.PubMedCrossRef

23.

Kikuchi T, Shimmei M. Effects of hyaluronan on proteoglycan metabolism of rabbit articular chondrocytes in culture. Jpn J Rheumatol. 1994;3:207–15.

24.

Kawasaki K, Ochi M, Uchio Y, Adachi N, Matsusaki M. Hyaluronic acid enhances proliferation and chondroitin sulfate synthesis in cultured chondrocytes embedded in collagen gels. J Cell Physiol. 1999;179:142–8.PubMedCrossRef

25.

Smith MM, Ghosh P. The synthesis of hyaluronic acid by human synovial fibroblast is influenced by the nature of the hyaluronate in the extracellular environment. Rheumatol Int. 1987;7:113–22.PubMedCrossRef

26.

Shimizu M, Yasuda T, Nakagawa T, Yamashita E, Julovi SM, Hiramitsu T, Nakamura T. Hyaluronan inhibits matrix metalloproteinase-1 production by rheumatoid synovial fibroblasts stimulated by proinflammatory cytokines. J Rheumatol. 2003;30:1164–72.PubMed

27.

Takahashi K, Goomer RS, Harwood F, Kubo T, Hirasawa Y, Amiel D. The effect of hyaluronan on matrix metalloproteinase-3, interleukin-1 beta, and tissue inhibitor of metalloproteinase-1 gene expression during the development of osteoarthritis. Osteoarthr Cartil. 1999;7:182–90.PubMedCrossRef

28.

Tanaka M, Masuko-Hongo K, Kato T, Nishioka K, Nakamura H. Suppressive effects of hyaluronan on MMP-1 and RANTES production from chondrocytes. Rheumatol Int. 2006;26:185–90.PubMedCrossRef

Title: Therapeutic effects of high molecular weight hyaluronan injections for tendinopathy in a rat model
Authors: Mamoru Yoshida
Hiroki Funasaki
Makoto Kubota
Keishi Marumo
Publication date: 01-01-2015
Publisher: Springer Japan
Published in: Journal of Orthopaedic Science / Issue 1/2015
Print ISSN: 0949-2658
Electronic ISSN: 1436-2023
DOI: https://doi.org/10.1007/s00776-014-0650-z

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Therapeutic effects of high molecular weight hyaluronan injections for tendinopathy in a rat model

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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