Abstract
Background
The pathogenesis of tendinopathy is complex and incompletely understood. Although significant advances have been made in terms of understanding the pathological changes in both the extracellular matrix and the cells involved, relatively little is known about the role of neuronal regulation in tendinopathy. The frequent mismatch between tendon pathology and pain may be explained, in part, by differences in the peripheral neuronal phenotype of patients.
Questions/purposes
The primary purpose of this review was to determine whether evidence exists of changes in the peripheral neuronal phenotype in painful human tendinopathy and, if so, to identify the associated histological and molecular changes. The secondary purpose was to determine if any changes in the peripheral neuronal phenotype reported correlate with pain symptoms.
Methods
We conducted a systematic review of the scientific literature using the PRISMA and Cochrane guidelines. The Medline and Embase databases were searched using specific search criteria. Only studies analyzing the peripheral tissue of patients with the clinical diagnosis of tendinopathy were included. Inclusion was agreed on by two independent researchers on review of abstracts or full text.
Results
Overall in the 27 included studies, there was clear evidence of changes in the peripheral neuronal phenotype in painful human tendinopathy. The excitatory glutaminergic system was significantly upregulated in seven studies, there was a significant increase in sensory neuropeptide expression in four studies, and there were significant changes in the molecular morphology of tenocytes, blood vessels, and nerves. In rotator cuff tendinopathy, substance P has been shown to correlate with pain and the neural density in the subacromial bursa has been shown to correlate with rest pain.
Conclusions
The peripheral neuronal phenotype is an important factor in the pathogenesis of painful human tendinopathy. Further research in this area specifically correlating tissue changes to clinical scores has great potential in further developing our understanding of the disease process.
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Acknowledgments
We thank the reviewers and editorial staff who have kindly helped in the production of this final manuscript.
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One or more of the authors are funded by the Musculoskeletal Biomedical Research Unit of the National Institute for Health Research (BD, SF, AC), the Jean Shanks Foundation (BD), and the Orthopaedic Research UK (BD).
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Appendices
Appendix 1. Study details
Number | Study | Year | Journal | Pathology | Primary tissue method |
|---|---|---|---|---|---|
1 | Alfredson et al. [3] | 2001 | Knee Surg Sports Traumatol Arthrosc | Achilles tendinopathy | Microdialysis via open incision |
2 | Alfredson et al. [4] | 2001 | J Orthop Res | Patellar tendinopathy | Microdialysis via open incision |
3 | Alfredson et al. [5] | 2000 | Acta Orthop Scand | Humeral epicondylitis | Microdialysis via open incision |
4 | Alfredson et al. [6] | 2003 | Knee Surg Sports Traumatol Arthrosc | Achilles tendinopathy | Open biopsy |
5 | Alfredson et al. [7] | 1999 | Knee Surg Sports Traumatol Arthrosc | Achilles tendinopathy | Microdialysis via open incision |
6 | Andersson et al. [9] | 2008 | Regul Pept | Achilles tendinopathy | Open biopsy |
7 | Bagge et al. [13] | 2009 | Histol Histopathol | Achilles tendinopathy | Open biopsy |
8 | Bagge et al. [12] | 2012 | Histol Histopathol | Achilles tendinopathy | Open biopsy |
9 | Bjorklund et al. [14] | 2011 | Plos One | Achilles tendinopathy | Open biopsy |
10 | Bjur et al. [15] | 2009 | Br J Sports Med | Achilles tendinopathy | Open biopsy |
11 | Bjur et al. [17] | 2008 | Cell Tissue Res | Achilles tendinopathy | Open biopsy |
12 | Bjur et al. [16] | 2008 | Histol Histopathol | Achilles tendinopathy | Open biopsy |
13 | Danielson et al. [23] | 2006 | Microsc Res Tech | Patellar tendinopathy | Open biopsy |
14 | Danielson et al. [24] | 2007 | Microsc Res Tech | Patellar tendinopathy | Open biopsy |
15 | Danielson et al. [25] | 2007 | Life Sci | Patellar tendinopathy | Open biopsy |
16 | Forsgren et al. [29] | 2005 | Regul Pept | Achilles and patellar tendinopathy | Open biopsy |
17 | Gotoh et al. [34] | 1998 | J Orthop Res | Rotator cuff disease | Open biopsy |
18 | Lian et al. [42] | 2006 | Am J Sports Med | Patellar tendinopathy | Open biopsy |
19 | Schizas et al. [53] | 2010 | Scand J Med Sci Sports | Patellar tendinopathy | Open biopsy |
20 | Schizas et al. [54] | 2012 | J Orthop Res | Patellar tendinopathy | Open biopsy |
21 | Schubert et al. [55] | 2005 | Ann Rheum Dis | Achilles tendinopathy | Open biopsy |
22 | Scott et al. [56] | 2008 | J Orthop Res | Achilles and patellar tendinopathy | Open biopsy |
23 | Singaraju et al. [58] | 2008 | J Shoulder Elbow Surg | Long head of biceps tendon | Open biopsy |
24 | Xu et al. [64] | 2011 | Sports Med Arthrosc | Rotator cuff disease | Open biopsy |
25 | Zeisig et al. [68] | 2009 | Br J Sports Med | Humeral epicondylitis | Open biopsy |
26 | Tomita et al. [61] | 1997 | J Orthop Surg | Rotator cuff disease | Open biopsy |
27 | Tamai et al. [59] | 2000 | Clin Orthop Relat Res | Rotator cuff disease | Open biopsy |
Appendix 2. Methodological quality scores for each study (q denotes question number and total denoting total score)
Author | Year | Journal | q1 | q2 | q3 | q4 | q5 | q6 | q7 | q8 | q9 | q10 | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Alfredson et al. [3] | 2001 | Knee Surg Sports Traumatol Arthrosc | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 10 |
Alfredson et al. [4] | 2001 | J Orthop Res | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 10 |
Alfredson et al. [5] | 2000 | Acta Orthop Scand | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 10 |
Alfredson et al. [6] | 2003 | Knee Surg Sports Traumatol Arthrosc | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 0 | 1 | 8 |
Alfredson et al. [7] | 1999 | Knee Surg Sports Traumatol Arthrosc | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 9 |
Andersson et al. [9] | 2008 | Regul Pept | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 10 |
Bagge et al. [13] | 2009 | Histol Histopathol | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 0 | 1 | 8 |
Bagge et al. [12] | 2012 | Histol Histopathol | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 0 | 1 | 8 |
Bjorklund et al. [14] | 2011 | Plos One | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 9 |
Bjur et al. [15] | 2009 | Br J Sports Med | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 1 | 9 |
Bjur et al. [17] | 2008 | Cell Tissue Res | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 0 | 0 | 7 |
Bjur et al. [16] | 2008 | Histol Histopathol | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 0 | 0 | 7 |
Danielson et al. [23] | 2006 | Microsc Res Tech | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 0 | 1 | 8 |
Danielson et al. [24] | 2007 | Microsc Res Tech | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 0 | 0 | 7 |
Danielson et al. [25] | 2007 | Life Sci | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 0 | 1 | 8 |
Forsgren et al. [29] | 2005 | Regul Pept | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 0 | 1 | 8 |
Gotoh et al. [34] | 1998 | J Orthop Res | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 10 |
Lian et al. [42] | 2006 | Am J Sports Med | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 10 |
Schizas et al. [53] | 2010 | Scand J Med Sci Sports | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 1 | 1 | 1 | 9 |
Schizas et al. [54] | 2012 | J Orthop Res | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 10 |
Schubert et al. [55] | 2005 | Ann Rheum Dis | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 9 |
Scott et al. [56] | 2008 | J Orthop Res | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 1 | 9 |
Singaraju et al. [58] | 2008 | J Shoulder Elbow Surg | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 1 | 0 | 1 | 8 |
Xu et al. [64] | 2011 | Sports Med Arthrosc | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 0 | 8 |
Zeisig et al. [68] | 2009 | Br J Sports Med | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 0 | 1 | 8 |
Tomita et al. [61] | 1997 | J Orthop Surg | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 1 | 0 | 0 | 7 |
Tamai et al. [59] | 2000 | Clin Orthop Relat Res | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 1 | 9 |
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Dean, B.J.F., Franklin, S.L. & Carr, A.J. The Peripheral Neuronal Phenotype is Important in the Pathogenesis of Painful Human Tendinopathy: A Systematic Review. Clin Orthop Relat Res 471, 3036–3046 (2013). https://doi.org/10.1007/s11999-013-3010-y
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DOI: https://doi.org/10.1007/s11999-013-3010-y