Pathogenesis and Development of Patellar Tendon Fibrosis in a Rabbit Overuse Model

Abstract

Background:

The pathogenesis of patellar tendon fibrosis caused by overuse remains unclear. In an effort to further investigate effective treatments for patellar tendon fibrosis attributed to overuse, it is necessary to construct a reliable animal model.

Purpose:

A rabbit patellar tendon fibrosis model was developed with the use of electrical stimulation to induce jumping. The pathogenesis and development of patellar tendon fibrosis were subsequently investigated with this model.

Study Design:

Controlled laboratory study.

Methods:

A total of 32 New Zealand White rabbits were randomly divided into a jumping group and a control group. Rabbits in the control group did not receive any treatment, while those in the jumping group jumped 150 times daily, 5 days per week. At 2, 4, 6, and 8 weeks after the initiation of treatment, the patellar tendons of 4 rabbits from each group were harvested and subjected to hematoxylin and eosin staining, immunohistochemical staining, and real-time polymerase chain reaction. The influence of jumping training on the expressions of histology- and fibrosis-related factors in the patellar tendon was assessed.

Results:

The histological changes of patellar tendon fibrosis in the jumping group were most pronounced at 4 weeks. When compared with the control group at corresponding time points, the mRNA and protein expressions of TGF-β1, CTGF, COL-I, and COL-III were upregulated significantly in the patellar tendon after jumping training for 4 weeks (P < .05). Intragroup comparison at different time points indicated that the mRNA and protein expressions of TGF-β1, COL-I, and COL-III were the highest at 4 weeks in the jumping group (P < .01).

Conclusion:

It was found that patellar tendon fibrosis occurred because of overuse and the peak changes occurred at 4 weeks. Jumping load increased the secretions of TGF-β1 and Smad3 in the patellar tendon, with CTGF upregulation and higher synthesis of COL-I and COL-III, which were considered the pathogenesis of fibrosis.

Clinical Relevance:

This study simulated the effects of jumping load on tendon fibrosis at different time points. Moreover, the time course relationship between jumping training and patellar tendon fibrosis in the rabbit model was determined, which provided a new animal model for the study of patellar tendon fibrosis.

Keywords

jumping patellar tendon fibrosis histology PCR rabbit patellar tendon fibrosis models

Get full access to this article

View all access options for this article.

References

Arno

Gauglitz

Barret

Jeschke

. New molecular medicine-based scar management strategies. Burns. 2014;40(4):539-551.

Asundi

King

Rempel

. Evaluation of gene expression through qRT-PCR in cyclically loaded tendons: an in vivo model. Eur J Appl Physiol. 2008;102:265-270.

Berglund

Hildebrand

Zhang

Hart

Wiig

. Neuropeptide, mast cell, and myofibroblast expression after rabbit deep flexor tendon repair. J Hand Surg Am. 2010;35(11):1842-1849.

Chen

Cheng

Jiang

. Cyclic mechanical stretching induces autophagic cell death in tenofibroblasts through activation of prostaglandin E2 production. Cell Physiol Biochem. 2015;36(1):24-33.

Chen

Puthanveetil

Feng

Matkovich

Dorn

Chakrabarti

. Cardiac miR-133a overexpression prevents early cardiac fibrosis in diabetes. J Cellular Molecular Med. 2014;18(3):415-421.

Dauty

Garraud

, et al. Jumper’s knee mechanical consequences in professional basketball players: the “camel’s back curve.”Eur J Appl Physiol. 2019;119(3):735-742.

Dideriksen

Sindby

Krogsgaard

Schjerling

Holm

Langberg

. Effect of acute exercise on patella tendon protein synthesis and gene expression. Springerplus. 2013;2(1):109.

Dirks

Richard

Fearon

, et al. Uphill treadmill running does not induce histopathological changes in the rat Achilles tendon. BMC Musculoskelet Disord. 2013;14:90.

Galatz

Gerstenfeld

Heber-Katz

Rodeo

. Tendon regeneration and scar formation: the concept of scarless healing. J Orthop Res. 2015;33(6):823-831.

10.

Gao

Fisher

Lambi

, et al. Increased serum and musculotendinous fibrogenic proteins following persistent low-grade inflammation in a rat model of long-term upper extremity overuse. PLoS One. 2013;8(8):e71875.

11.

Huang

Gao

Huang

Guo

. Effect of cyclic training model on terminal structure of rabbit Achilles tendon: an experimental study. Med J Chin PLA. 2012;37(5):515-518.

12.

Hyer

. TGF-β and CTGF Regulation of Extracellular Matrix Synthesis in Tissue Fibrosis: Analysis of In Vitro and In Vivo Models. Charleston, SC: Medical University of South Carolina; 2002.

13.

Ihn

. Autocrine TGF-beta signaling in the pathogenesis of systemic sclerosis. J Dermatol Sci. 2008;49(2):103-113.

14.

Janssen

Steele

Munro

Brown

NAT

. Previously identified patellar tendinopathy risk factors differ between elite and sub-elite volleyball players. Scand J Med Sci Sports. 2015;25(3):308-314.

15.

Jiang

. Characteristics of patella-patellar tendon junction in histomorphology and expression of related growth factors under the condition of continuous jumping. Tianjin Univ Sport. 2016;31(2):141-146.

16.

Jiang

. Establishment of Animal Model of Patella–Patellar Tendon Junction Injury From Jumping and Effect of Post-exercise Cryotherapy on Injury. Beijing, China: Beijing Sport University; 2015.

17.

Jiang

Chun

Wang

Xiong

. Effect of transforming growth factor-beta3 on the expression of Smad3 and Smad7 in tenocytes. Mol Med Rep. 2016;13(4):3567-3573.

18.

Kawakami

Ihn

Smith

LeRoy

Trojanowska

. Increased expression of TGF-beta receptors by scleroderma fibroblasts: evidence for contribution of autocrine TGF-beta signaling to scleroderma phenotype. J Invest Dermatol. 1998;110(1):47-51.

19.

Kjaer

Langberg

Heinemeier

, et al. From mechanical loading to collagen synthesis, structural changes and function in human tendon. Scand J Med Sci Sports. 2009;19(4):500-510.

20.

Lau

Lam

. The CCN family of angiogenic regulators: the integrin connection. Exp Cell Res. 1999;248(1):44-57.

21.

Leung

Chong

Chow

, et al. A comparative study on the biomechanical and histological properties of bone-to-bone, bone-to-tendon, and tendon-to-tendon healing: an Achilles tendon-calcaneus model in goats. Am J Sports Med. 2015;43(6):1413-1421.

22.

Loiselle

Yukata

Geary

, et al. Development of antisense oligonucleotide (ASO) technology against Tgf-beta signaling to prevent scarring during flexor tendon repair. J Orthop Res. 2015;33(6):859-866.

23.

Longo

Franceschi

Ruzzini

, et al. Histopathology of the supraspinatus tendon in rotator cuff tears. Am J Sports Med. 2008;36(3):533-538.

24.

Maffulli

Longo

Franceschi

Rabitti

Denaro

. Movin and Bonar scores assess the same characteristics of tendon histology. Clin Orthop Relat Res. 2008;466(7):1605-1611.

25.

Maffulli

Testa

Capasso

, et al. Similar histopathological picture in males with Achilles and patellar tendinopathy. Med Sci Sports Exerc. 2004;36(9):1470-1475.

26.

Majewski

Porter

Betz

, et al. Improvement of tendon repair using muscle grafts transduced with TGF-beta1 cDNA. Eur Cell Mater. 2012;23:94-101.

27.

Malliaras

Barton

Reeves

Langberg

. Achilles and patellar tendinopathy loading programmes: a systematic review comparing clinical outcomes and identifying potential mechanisms for effectiveness. Sports Med. 2013;43(4):267-286.

28.

Megiorni

Cialfi

Cimino

, et al. Elevated levels of miR-145 correlate with SMAD3 down-regulation in cystic fibrosis patients. J Cystic Fibrosis. 2013;12(6):797-802.

29.

Muller

Todorov

Heisterbach

Martin

Majewski

. Tendon healing: an overview of physiology, biology, and pathology of tendon healing and systematic review of state of the art in tendon bioengineering. Knee Surg Sports Traumatol Arthrosc. 2015;23(7):2097-2105.

30.

Nakama

King

Abrahamsson

Rempel

. VEGF, VEGFR-1, and CTGF cell densities in tendon are increased with cyclical loading: an in vivo tendinopathy model. J Orthop Res. 2006;24(3):393-400.

31.

Nourissat

Berenbaum

Duprez

. Tendon injury: from biology to tendon repair. Nat Rev Rheumatol. 2015;11(4):223-233.

32.

Parkinson

Samiric

Ilic

Cook

Feller

Handley

. Change in proteoglycan metabolism is a characteristic of human patellar tendinopathy. Arthritis Rheum. 2010;62(10):3028-3035.

33.

Parks

McFaline-Figueroa

Coogan

, et al. Supraspinatus tendon overuse results in degenerative changes to tendon insertion region and adjacent humeral cartilage in a rat model. J Orthop Res. 2017;35(9):1910-1918.

34.

Paula

Francisco

Salvini

. Eccentric training as a new approach for rotator cuff tendinopathy: review and perspectives. World J Orthop. 2014;5(5):634-644.

35.

Pohlers

Brenmoehl

Loffler

, et al. TGF-beta and fibrosis in different organs—molecular pathway imprints. Biochim Biophys Acta. 2009;1792(8):746-756.

36.

Ponticos

Holmes

Xun

, et al. Pivotal role of connective tissue growth factor in lung fibrosis: MAPK-dependent transcriptional activation of type I collagen. Arthritis Rheum. 2009;60(7):2142-2155.

37.

Rees

Wilson

Wolman

. Current concepts in the management of tendon disorders. Rheumatology (Oxford). 2006;45(5):508-521.

38.

Saithna

Gogna

Baraza

Modi

Spencer

. Eccentric exercise protocols for patella tendinopathy: should we really be withdrawing athletes from sport? A systematic review. Open Orthop J. 2012;6:553-557.

39.

Samiric

Parkinson

Ilic

Cook

Feller

Handley

. Changes in the composition of the extracellular matrix in patellar tendinopathy. Matrix Biol. 2009;28(4):230-236.

40.

Sodersten

Hultenby

Heinegard

Johnston

Ekman

. Immunolocalization of collagens (I and III) and cartilage oligomeric matrix protein in the normal and injured equine superficial digital flexor tendon. Connect Tissue Res. 2013;54(1):62-69.

41.

Sonnabend

Howlett

Young

. Histological evaluation of repair of the rotator cuff in a primate model. J Bone Joint Surg Br. 2010;92(4):586-594.

42.

Sun

Andarawis-Puri

, et al. Cycle-dependent matrix remodeling gene expression response in fatigue-loaded rat patellar tendons. J Orthop Res. 2010;28(10):1380-1386.

43.

Tan

Chan

. Achilles and patellar tendinopathy: current understanding of pathophysiology and management. Disabil Rehabil. 2008;30(20-22):1608-1615.

44.

van Almen

Verhesen

van Leeuwen

, et al. MicroRNA-18 and microRNA-19 regulate CTGF and TSP-1 expression in age-related heart failure. Aging Cell. 2011;10(5):769-779.

45.

Van der

Worp H

de Poel

Diercks

van den Akker-Scheek

Zwerver

. Jumper’s knee or lander’s knee? A systematic review of the relation between jump biomechanics and patellar tendinopathy. Int J Sports Med. 2014;35(8):714-722.

46.

Wang

Gao

Xiong

Liu

. VEGF and BFGF expression and histological characteristics of the bone-tendon junction during acute injury healing. J Sports Sci Med. 2014;13(1):15-21.

47.

Warden

. Animal models for the study of tendinopathy. Br J Sports Med. 2007;41(4):232-240.

48.

Yang

Zheng

Chen

. Regulatory mechanisms of the molecular pathways in fibrosis induced by microRNAs. Chin Med J (Engl). 2016;129(19):2365-2372.

49.

Yang

Crawford

Wang

. Proliferation and collagen production of human patellar tendon fibroblasts in response to cyclic uniaxial stretching in serum-free conditions. J Biomech. 2004;37(10):1543-1550.

50.

Zhang

Xiao

Wang

Yang

Dai

. Differential expression and therapeutic efficacy of microRNA-346 in diabetic nephropathy mice. Exp Ther Med. 2015;10(1):106-112.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.67 MB