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Published in: BMC Musculoskeletal Disorders 1/2016

Open Access 01-12-2016 | Research article

Coordinate and synergistic effects of extensive treadmill exercise and ovariectomy on articular cartilage degeneration

Authors: Kazumasa Miyatake, Takeshi Muneta, Miyoko Ojima, Jun Yamada, Yu Matsukura, Kahaer Abula, Ichiro Sekiya, Kunikazu Tsuji

Published in: BMC Musculoskeletal Disorders | Issue 1/2016

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Abstract

Background

Although osteoarthritis (OA) is a multifactorial disease, little has been reported regarding the cooperative interaction among these factors on cartilage metabolism. Here we examined the synergistic effect of ovariectomy (OVX) and excessive mechanical stress (forced running) on articular cartilage homeostasis in a mouse model resembling a human postmenopausal condition.

Methods

Mice were randomly divided into four groups, I: Sham, II: OVX, III: Sham and forced running (60 km in 6 weeks), and IV: OVX and forced running. Histological and immunohistochemical analyses were performed to evaluate the degeneration of articular cartilage and synovitis in the knee joint. Morphological changes of subchondral bone were analyzed by micro-CT.

Results

Micro-CT analyses showed significant loss of metaphyseal trabecular bone volume/tissue volume (BV/TV) after OVX as described previously. Forced running increased the trabecular BV/TV in all mice. In the epiphyseal region, no visible alteration in bone morphology or osteophyte formation was observed in any of the four groups. Histological analysis revealed that OVX or forced running respectively had subtle effects on cartilage degeneration. However, the combination of OVX and forced running synergistically enhanced synovitis and articular cartilage degeneration. Although morphological changes in chondrocytes were observed during OA initiation, no signs of bone marrow edema were observed in any of the four experimental groups.

Conclusion

We report the coordinate and synergistic effects of extensive treadmill exercise and ovariectomy on articular cartilage degeneration. Since no surgical procedure was performed on the knee joint directly in this model, this model is useful in addressing the molecular pathogenesis of naturally occurring OA.
Literature
1.
go back to reference Johnson VL, Hunter DJ. The epidemiology of osteoarthritis. Best Pract Res Clin Rheumatol. 2014;28:5–15.CrossRefPubMed Johnson VL, Hunter DJ. The epidemiology of osteoarthritis. Best Pract Res Clin Rheumatol. 2014;28:5–15.CrossRefPubMed
2.
go back to reference Furman BD, Strand J, Hembree WC, et al. Joint degeneration following closed intraarticular fracture in the mouse knee: a model of posttraumatic arthritis. J Orthop Res. 2007;25:578–92.CrossRefPubMed Furman BD, Strand J, Hembree WC, et al. Joint degeneration following closed intraarticular fracture in the mouse knee: a model of posttraumatic arthritis. J Orthop Res. 2007;25:578–92.CrossRefPubMed
3.
go back to reference Kamekura S, Hoshi K, Shimoaka T, et al. Osteoarthritis development in novel experimental mouse models induced by knee joint instability. Osteoarthritis Cartilage. 2005;13:632–41.CrossRefPubMed Kamekura S, Hoshi K, Shimoaka T, et al. Osteoarthritis development in novel experimental mouse models induced by knee joint instability. Osteoarthritis Cartilage. 2005;13:632–41.CrossRefPubMed
4.
go back to reference Sekiya I, Tang T, Hayashi M, et al. Periodic knee injections of BMP-7 delay cartilage degeneration induced by excessive running in rats. J Orthop Res. 2009;27:1088–92.CrossRefPubMed Sekiya I, Tang T, Hayashi M, et al. Periodic knee injections of BMP-7 delay cartilage degeneration induced by excessive running in rats. J Orthop Res. 2009;27:1088–92.CrossRefPubMed
5.
go back to reference Pelletier JP, Martel-Pelletier J, Abramson SB. Osteoarthritis, an inflammatory disease: potential implication for the selection of new therapeutic targets. Arthritis Rheum. 2001;44:1237–47.CrossRefPubMed Pelletier JP, Martel-Pelletier J, Abramson SB. Osteoarthritis, an inflammatory disease: potential implication for the selection of new therapeutic targets. Arthritis Rheum. 2001;44:1237–47.CrossRefPubMed
8.
go back to reference Sniekers YH, Weinans H, Bierma-Zeinstra SM, et al. Animal models for osteoarthritis: the effect of ovariectomy and estrogen treatment - a systematic approach. Osteoarthritis Cartilage. 2008;16:533–41.CrossRefPubMed Sniekers YH, Weinans H, Bierma-Zeinstra SM, et al. Animal models for osteoarthritis: the effect of ovariectomy and estrogen treatment - a systematic approach. Osteoarthritis Cartilage. 2008;16:533–41.CrossRefPubMed
9.
go back to reference Yoshimura N, Muraki S, Oka H, et al. Prevalence of knee osteoarthritis, lumbar spondylosis, and osteoporosis in Japanese men and women: the research on osteoarthritis/osteoporosis against disability study. J Bone Miner Metab. 2009;27:620–8.CrossRefPubMed Yoshimura N, Muraki S, Oka H, et al. Prevalence of knee osteoarthritis, lumbar spondylosis, and osteoporosis in Japanese men and women: the research on osteoarthritis/osteoporosis against disability study. J Bone Miner Metab. 2009;27:620–8.CrossRefPubMed
10.
go back to reference Dominick KL, Baker TA. Racial and ethnic differences in osteoarthritis: prevalence, outcomes, and medical care. Ethn Dis. 2004;14:558–66.PubMed Dominick KL, Baker TA. Racial and ethnic differences in osteoarthritis: prevalence, outcomes, and medical care. Ethn Dis. 2004;14:558–66.PubMed
11.
go back to reference Jiang L, Tian W, Wang Y, et al. Body mass index and susceptibility to knee osteoarthritis: a systematic review and meta-analysis. Joint Bone Spine. 2012;79:291–7.CrossRefPubMed Jiang L, Tian W, Wang Y, et al. Body mass index and susceptibility to knee osteoarthritis: a systematic review and meta-analysis. Joint Bone Spine. 2012;79:291–7.CrossRefPubMed
12.
go back to reference Lohmander LS, Gerhardsson de Verdier M, Rollof J, et al. Incidence of severe knee and hip osteoarthritis in relation to different measures of body mass: a population-based prospective cohort study. Ann Rheum Dis. 2009;68:490–6.CrossRefPubMed Lohmander LS, Gerhardsson de Verdier M, Rollof J, et al. Incidence of severe knee and hip osteoarthritis in relation to different measures of body mass: a population-based prospective cohort study. Ann Rheum Dis. 2009;68:490–6.CrossRefPubMed
13.
go back to reference Wolfe F, Lane NE. The longterm outcome of osteoarthritis: rates and predictors of joint space narrowing in symptomatic patients with knee osteoarthritis. J Rheumatol. 2002;29:139–46.PubMed Wolfe F, Lane NE. The longterm outcome of osteoarthritis: rates and predictors of joint space narrowing in symptomatic patients with knee osteoarthritis. J Rheumatol. 2002;29:139–46.PubMed
14.
go back to reference Le Graverand MP, Brandt K, Mazzuca SA, et al. Progressive increase in body mass index is not associated with a progressive increase in joint space narrowing in obese women with osteoarthritis of the knee. Ann Rheum Dis. 2009;68:1734–8.CrossRefPubMed Le Graverand MP, Brandt K, Mazzuca SA, et al. Progressive increase in body mass index is not associated with a progressive increase in joint space narrowing in obese women with osteoarthritis of the knee. Ann Rheum Dis. 2009;68:1734–8.CrossRefPubMed
15.
go back to reference Yusuf E, Bijsterbosch J, Slagboom PE, et al. Association between several clinical and radiological determinants with long-term clinical progression and good prognosis of lower limb osteoarthritis. PLoS One. 2011;6:e25426.CrossRefPubMedPubMedCentral Yusuf E, Bijsterbosch J, Slagboom PE, et al. Association between several clinical and radiological determinants with long-term clinical progression and good prognosis of lower limb osteoarthritis. PLoS One. 2011;6:e25426.CrossRefPubMedPubMedCentral
16.
go back to reference Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat Rev Rheumatol. 2010;6:625–35.CrossRefPubMed Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat Rev Rheumatol. 2010;6:625–35.CrossRefPubMed
17.
go back to reference Roemer FW, Nevitt MC, Felson DT, et al. Predictive validity of within-grade scoring of longitudinal changes of MRI-based cartilage morphology and bone marrow lesion assessment in the tibio-femoral joint--the MOST study. Osteoarthritis Cartilage. 2012;20:1391–8.CrossRefPubMed Roemer FW, Nevitt MC, Felson DT, et al. Predictive validity of within-grade scoring of longitudinal changes of MRI-based cartilage morphology and bone marrow lesion assessment in the tibio-femoral joint--the MOST study. Osteoarthritis Cartilage. 2012;20:1391–8.CrossRefPubMed
18.
go back to reference Felson DT, Niu J, Guermazi A, et al. Correlation of the development of knee pain with enlarging bone marrow lesions on magnetic resonance imaging. Arthritis Rheum. 2007;56:2986–92.CrossRefPubMed Felson DT, Niu J, Guermazi A, et al. Correlation of the development of knee pain with enlarging bone marrow lesions on magnetic resonance imaging. Arthritis Rheum. 2007;56:2986–92.CrossRefPubMed
20.
go back to reference McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage. 2014;22:363–88.CrossRefPubMed McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage. 2014;22:363–88.CrossRefPubMed
21.
go back to reference Ma HL, Blanchet TJ, Peluso D, et al. Osteoarthritis severity is sex dependent in a surgical mouse model. Osteoarthritis Cartilage. 2007;15:695–700.CrossRefPubMed Ma HL, Blanchet TJ, Peluso D, et al. Osteoarthritis severity is sex dependent in a surgical mouse model. Osteoarthritis Cartilage. 2007;15:695–700.CrossRefPubMed
22.
go back to reference Williams JM, Felten DL, Peterson RG, O’Connor BL. Effects of surgically induced instability on rat knee articular cartilage. J Anat. 1982;134:103–9.PubMedPubMedCentral Williams JM, Felten DL, Peterson RG, O’Connor BL. Effects of surgically induced instability on rat knee articular cartilage. J Anat. 1982;134:103–9.PubMedPubMedCentral
23.
go back to reference Guzman RE, Evans MG, Bove S, et al. Mono-iodoacetate-induced histologic changes in subchondral bone and articular cartilage of rat femorotibial joints: an animal model of osteoarthritis. Toxicol Pathol. 2003;31:619–24.CrossRefPubMed Guzman RE, Evans MG, Bove S, et al. Mono-iodoacetate-induced histologic changes in subchondral bone and articular cartilage of rat femorotibial joints: an animal model of osteoarthritis. Toxicol Pathol. 2003;31:619–24.CrossRefPubMed
24.
go back to reference Yamada J, Tsuji K, Miyatake K, et al. Follistatin alleviates synovitis and articular cartilage degeneration induced by carrageenan. Int J Inflamm. 2014;2014:959271.CrossRef Yamada J, Tsuji K, Miyatake K, et al. Follistatin alleviates synovitis and articular cartilage degeneration induced by carrageenan. Int J Inflamm. 2014;2014:959271.CrossRef
25.
go back to reference Brown TD, Johnston RC, Saltzman CL, et al. Posttraumatic osteoarthritis: a first estimate of incidence, prevalence, and burden of disease. J Orthop Trauma. 2006;20:739–44.CrossRefPubMed Brown TD, Johnston RC, Saltzman CL, et al. Posttraumatic osteoarthritis: a first estimate of incidence, prevalence, and burden of disease. J Orthop Trauma. 2006;20:739–44.CrossRefPubMed
26.
go back to reference Abula K, Muneta T, Miyatake K, et al. Elimination of BMP7 from the developing limb mesenchyme leads to articular cartilage degeneration and synovial inflammation with increased age. FEBS Lett. 2015;589:1240–8.CrossRefPubMed Abula K, Muneta T, Miyatake K, et al. Elimination of BMP7 from the developing limb mesenchyme leads to articular cartilage degeneration and synovial inflammation with increased age. FEBS Lett. 2015;589:1240–8.CrossRefPubMed
27.
go back to reference Hayami T, Pickarski M, Zhuo Y, et al. Characterization of articular cartilage and subchondral bone changes in the rat anterior cruciate ligament transection and meniscectomized models of osteoarthritis. Bone. 2006;38:234–43.CrossRefPubMed Hayami T, Pickarski M, Zhuo Y, et al. Characterization of articular cartilage and subchondral bone changes in the rat anterior cruciate ligament transection and meniscectomized models of osteoarthritis. Bone. 2006;38:234–43.CrossRefPubMed
28.
go back to reference Im GI, Kim MK. The relationship between osteoarthritis and osteoporosis. J Bone Miner Metab. 2014;32:101–9.CrossRefPubMed Im GI, Kim MK. The relationship between osteoarthritis and osteoporosis. J Bone Miner Metab. 2014;32:101–9.CrossRefPubMed
29.
go back to reference North American Menopause Society. Estrogen and progestogen use in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause. 2010;17:242–55.CrossRef North American Menopause Society. Estrogen and progestogen use in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause. 2010;17:242–55.CrossRef
30.
go back to reference Takasu N. Experimental study on the effect of forced running on occurrence of osteoarthritis in the knee of C 57 BL mice. Nihon Seikeigeka Gakkai Zasshi. 1992;66:1165–75.PubMed Takasu N. Experimental study on the effect of forced running on occurrence of osteoarthritis in the knee of C 57 BL mice. Nihon Seikeigeka Gakkai Zasshi. 1992;66:1165–75.PubMed
31.
go back to reference Hyttinen M, Arokoski J, Parkkinen J, et al. Age matters: collagen birefringence of superficial articular cartilage is increased in young guinea-pigs but decreased in older animals after identical physiological type of joint loading. Osteoarthr Cartil. 2001;9:694–701.CrossRefPubMed Hyttinen M, Arokoski J, Parkkinen J, et al. Age matters: collagen birefringence of superficial articular cartilage is increased in young guinea-pigs but decreased in older animals after identical physiological type of joint loading. Osteoarthr Cartil. 2001;9:694–701.CrossRefPubMed
32.
go back to reference Lugo L, Villalvilla A, Largo R, et al. Selective estrogen receptor modulators (SERMs): new alternatives for osteoarthritis? Maturitas. 2014;77:380–4.CrossRefPubMed Lugo L, Villalvilla A, Largo R, et al. Selective estrogen receptor modulators (SERMs): new alternatives for osteoarthritis? Maturitas. 2014;77:380–4.CrossRefPubMed
33.
34.
go back to reference Cavailles V. Estrogens and receptors: an evolving concept. Climacteric. 2002;5 Suppl 2:20–6.PubMed Cavailles V. Estrogens and receptors: an evolving concept. Climacteric. 2002;5 Suppl 2:20–6.PubMed
35.
go back to reference Simopoulou T, Malizos KN, Iliopoulos D, et al. Differential expression of leptin and leptin’s receptor isoform (Ob-Rb) mRNA between advanced and minimally affected osteoarthritic cartilage; effect on cartilage metabolism. Osteoarthritis Cartilage. 2007;15:872–83.CrossRefPubMed Simopoulou T, Malizos KN, Iliopoulos D, et al. Differential expression of leptin and leptin’s receptor isoform (Ob-Rb) mRNA between advanced and minimally affected osteoarthritic cartilage; effect on cartilage metabolism. Osteoarthritis Cartilage. 2007;15:872–83.CrossRefPubMed
36.
go back to reference Ryu JH, Yang S, Shin Y, et al. Interleukin‐6 plays an essential role in hypoxia‐inducible factor 2α–induced experimental osteoarthritic cartilage destruction in mice. Arthritis Rheum. 2011;63:2732–43.CrossRefPubMed Ryu JH, Yang S, Shin Y, et al. Interleukin‐6 plays an essential role in hypoxia‐inducible factor 2α–induced experimental osteoarthritic cartilage destruction in mice. Arthritis Rheum. 2011;63:2732–43.CrossRefPubMed
37.
go back to reference Sniekers YH, Weinans H, van Osch GJ, van Leeuwen JP. Oestrogen is important for maintenance of cartilage and subchondral bone in a murine model of knee osteoarthritis. Arthritis Res Ther. 2010;12:R182.CrossRefPubMedPubMedCentral Sniekers YH, Weinans H, van Osch GJ, van Leeuwen JP. Oestrogen is important for maintenance of cartilage and subchondral bone in a murine model of knee osteoarthritis. Arthritis Res Ther. 2010;12:R182.CrossRefPubMedPubMedCentral
38.
go back to reference Lapvetelainen T, Hyttinen M, Lindblom J, et al. More knee joint osteoarthritis (OA) in mice after inactivation of one allele of type II procollagen gene but less OA after lifelong voluntary wheel running exercise. Osteoarthritis Cartilage. 2001;9:152–60.CrossRefPubMed Lapvetelainen T, Hyttinen M, Lindblom J, et al. More knee joint osteoarthritis (OA) in mice after inactivation of one allele of type II procollagen gene but less OA after lifelong voluntary wheel running exercise. Osteoarthritis Cartilage. 2001;9:152–60.CrossRefPubMed
39.
go back to reference Lapvetelainen T, Hyttinen MM, Saamanen AM, et al. Lifelong voluntary joint loading increases osteoarthritis in mice housing a deletion mutation in type II procollagen gene, and slightly also in non-transgenic mice. Ann Rheum Dis. 2002;61:810–7.CrossRefPubMedPubMedCentral Lapvetelainen T, Hyttinen MM, Saamanen AM, et al. Lifelong voluntary joint loading increases osteoarthritis in mice housing a deletion mutation in type II procollagen gene, and slightly also in non-transgenic mice. Ann Rheum Dis. 2002;61:810–7.CrossRefPubMedPubMedCentral
40.
go back to reference Brisby H, Papadimitriou N, Runesson E, Sasaki N, Lindahl A, Henriksson HB. Moderate physical exercise results in increased cell activity in articular cartilage of the knee joint in rats. Cells Tissues Organs. 2013;198(3):237–48.CrossRefPubMed Brisby H, Papadimitriou N, Runesson E, Sasaki N, Lindahl A, Henriksson HB. Moderate physical exercise results in increased cell activity in articular cartilage of the knee joint in rats. Cells Tissues Organs. 2013;198(3):237–48.CrossRefPubMed
41.
go back to reference Chen X, Macica CM, Nasiri A, Broadus AE. Regulation of articular chondrocyte proliferation and differentiation by indian hedgehog and parathyroid hormone-related protein in mice. Arthritis Rheum. 2008;58(12):3788–97.CrossRefPubMedPubMedCentral Chen X, Macica CM, Nasiri A, Broadus AE. Regulation of articular chondrocyte proliferation and differentiation by indian hedgehog and parathyroid hormone-related protein in mice. Arthritis Rheum. 2008;58(12):3788–97.CrossRefPubMedPubMedCentral
42.
43.
go back to reference Blom AB, van Lent PL, Libregts S, et al. Crucial role of macrophages in matrix metalloproteinase-mediated cartilage destruction during experimental osteoarthritis: involvement of matrix metalloproteinase 3. Arthritis Rheum. 2007;56:147–57.CrossRefPubMed Blom AB, van Lent PL, Libregts S, et al. Crucial role of macrophages in matrix metalloproteinase-mediated cartilage destruction during experimental osteoarthritis: involvement of matrix metalloproteinase 3. Arthritis Rheum. 2007;56:147–57.CrossRefPubMed
44.
go back to reference Li J, Gorski DJ, Anemaet W, et al. Hyaluronan injection in murine osteoarthritis prevents TGFbeta 1-induced synovial neovascularization and fibrosis and maintains articular cartilage integrity by a CD44-dependent mechanism. Arthritis Res Ther. 2012;14:R151.CrossRefPubMedPubMedCentral Li J, Gorski DJ, Anemaet W, et al. Hyaluronan injection in murine osteoarthritis prevents TGFbeta 1-induced synovial neovascularization and fibrosis and maintains articular cartilage integrity by a CD44-dependent mechanism. Arthritis Res Ther. 2012;14:R151.CrossRefPubMedPubMedCentral
45.
go back to reference Kawaguchi H. Endochondral ossification signals in cartilage degradation during osteoarthritis progression in experimental mouse models. Mol Cells. 2008;25:1–6.PubMed Kawaguchi H. Endochondral ossification signals in cartilage degradation during osteoarthritis progression in experimental mouse models. Mol Cells. 2008;25:1–6.PubMed
46.
go back to reference Tessier JJ, Bowyer J, Brownrigg NJ, et al. Characterisation of the guinea pig model of osteoarthritis by in vivo three-dimensional magnetic resonance imaging. Osteoarthritis Cartilage. 2003;11:845–53.CrossRefPubMed Tessier JJ, Bowyer J, Brownrigg NJ, et al. Characterisation of the guinea pig model of osteoarthritis by in vivo three-dimensional magnetic resonance imaging. Osteoarthritis Cartilage. 2003;11:845–53.CrossRefPubMed
47.
go back to reference Botter SM, van Osch GJ, Clockaerts S, et al. Osteoarthritis induction leads to early and temporal subchondral plate porosity in the tibial plateau of mice: an in vivo microfocal computed tomography study. Arthritis Rheum. 2011;63:2690–9.CrossRefPubMed Botter SM, van Osch GJ, Clockaerts S, et al. Osteoarthritis induction leads to early and temporal subchondral plate porosity in the tibial plateau of mice: an in vivo microfocal computed tomography study. Arthritis Rheum. 2011;63:2690–9.CrossRefPubMed
48.
go back to reference Babatunde OO, Forsyth JJ, Gidlow CJ. A meta-analysis of brief high-impact exercises for enhancing bone health in premenopausal women. Osteoporos Int. 2012;23:109–19.CrossRefPubMed Babatunde OO, Forsyth JJ, Gidlow CJ. A meta-analysis of brief high-impact exercises for enhancing bone health in premenopausal women. Osteoporos Int. 2012;23:109–19.CrossRefPubMed
49.
go back to reference Iwamoto J, Takeda T, Ichimura S. Effect of exercise on tibial and lumbar vertebral bone mass in mature osteopenic rats: bone histomorphometry study. J Orthop Sci. 1998;3:257–63.CrossRefPubMed Iwamoto J, Takeda T, Ichimura S. Effect of exercise on tibial and lumbar vertebral bone mass in mature osteopenic rats: bone histomorphometry study. J Orthop Sci. 1998;3:257–63.CrossRefPubMed
50.
go back to reference Hannan MT, Felson DT, Anderson JJ, et al. Estrogen use and radiographic osteoarthritis of the knee in women. The Framingham Osteoarthritis Study. Arthritis Rheum. 1990;33:525–32.CrossRefPubMed Hannan MT, Felson DT, Anderson JJ, et al. Estrogen use and radiographic osteoarthritis of the knee in women. The Framingham Osteoarthritis Study. Arthritis Rheum. 1990;33:525–32.CrossRefPubMed
51.
go back to reference Spector TD, Nandra D, Hart DJ, Doyle DV. Is hormone replacement therapy protective for hand and knee osteoarthritis in women?: The Chingford Study. Ann Rheum Dis. 1997;56:432–4.CrossRefPubMedPubMedCentral Spector TD, Nandra D, Hart DJ, Doyle DV. Is hormone replacement therapy protective for hand and knee osteoarthritis in women?: The Chingford Study. Ann Rheum Dis. 1997;56:432–4.CrossRefPubMedPubMedCentral
Metadata
Title
Coordinate and synergistic effects of extensive treadmill exercise and ovariectomy on articular cartilage degeneration
Authors
Kazumasa Miyatake
Takeshi Muneta
Miyoko Ojima
Jun Yamada
Yu Matsukura
Kahaer Abula
Ichiro Sekiya
Kunikazu Tsuji
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Musculoskeletal Disorders / Issue 1/2016
Electronic ISSN: 1471-2474
DOI
https://doi.org/10.1186/s12891-016-1094-8

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