Melissa Cullum

Introduction. Carpal Tunnel Syndrome (CTS), a neuropathic pain condition, is the most common peripheral neuropathy.²Inflammatory actors, such as Platelet Derived Growth Factor (PDGF) and Transforming Growth Factor- β (TGF- β), have been isolated as inflammatory mediators in CTS.^1,2,3,4 Some also focus on the regulation of Nerve Growth Factor (NGF) and Cyclooxygenase-2 (COX-2) in respect to TGF- β. Methods. A comprehensive set of blood inflammatory mediators were observed at both mRNA and protein levels in the active stage of nerve injury and in recovery.² Fifty-five patients with CTS were observed, as were 21 healthy control participants.² Subsynovial connective tissue (SSCT) from 26 idiopathic CTS patients was compared to SSCT from 10 human cadaver controls with no diagnosis of CTS.³ Immunohistochemistry was used to assess levels of TGF-β1.³ Forty-three SSCT samples were analyzed from 35 patients prior to their CTS release surgery.⁴ Correlations between COX-2, NGF and TGF-β were evaluated with q-PCR.⁴ Chemical inhibitors for PDGFRs were used to target receptor signaling for primary fibroblasts.⁷  Additionally, 110 trial participants were encouraged to do moderate-to vigorous physical activity for at least 30 minutes daily for 12 weeks.⁶ Venous blood samples were collected from 38 participants of the trial and a panel of 24 immune activity inflammatory biomarkers was measured.⁶ Blood sampling was extensive both prior, during and after the 12 weeks.⁶ Results.  TGF- β levels were increased in the serum levels of CTS patients (adjusted P = 0.016).² There also was a strong positive relationship between TGF-β1 and Connective Tissue GF expression (R2 = 0.80, p < 0.01) and a moderate positive correlation with TGF-β1 and collagen-3 expression, a fibrotic factor(R2 = 0.49, p < 0.01).³  Expression of COX-2 and NGF positively correlated with TGF-β mRNA expression in the SSCTs of CTS patients (COX-2, r = 0.629, p < 0.001; NGF, r = 0.521, p < 0.001) .⁴ PDGFR inhibition significantly decreased collagen-3 (p < 0.05).^7,8  Significant exercise-associated reductions in levels of TGF-β1 (p = 0.00053) was found.⁶  Conclusions. Treatments currently offered for CTS are not sufficient. Multiple trials show that TGF-β plays a large role in the fibrotic and inflammatory mediators in CTS.^2,3,4 PDGFR seems to have similar roles.^1,2,7,8  This suggests that therapeutic targets can expand to more than just CTS releasing surgery and basic physical therapy, the protocol.²  Clinical trials involving drugs that target these growth factors are worth exploring.⁸ Surging data also suggests that daily moderate-vigorous exercise leads to decreased inflammatory markers found in conditions like CTS.⁶

1. Saito Y, Chikenji T, Ozasa Y, et al. PDGFR Signaling Mediates Hyperproliferation and Fibrotic Responses of Subsynovial Connective Tissue Cells in Idiopathic Carpal Tunnel Syndrome. Sci Rep. 2017;7(1):16192. Published 2017 Nov 23. doi:10.1038/s41598-017-16443-w
2. Sandy-Hindmarch O, Bennett DL, Wiberg A, Furniss D, Baskozos G, Schmid AB. Systemic inflammatory markers in neuropathic pain, nerve injury, and recovery. Pain. 2022;163(3):526-537. doi:10.1097/j.pain.0000000000002386
3. Chikenji T, Gingery A, Zhao C, et al. Transforming growth factor-β (TGF-β) expression is increased in the Subsynovial connective tissues of patients with idiopathic carpal tunnel syndrome. J Orthop Res. 2014;32(1):116-122. doi:10.1002/jor.22485
4. Nakawaki M, Uchida K, Onuma K, et al. Transforming Growth Factor-Beta (TGF-Β) Regulates Nerve Growth Factor and Cyclooxygenase-2 Expression in Subsynovial Connective Tissue in Patients with Carpal Tunnel Syndrome. IAOS. Published online September 19, 2018. doi:10.23937/iaos-2017/1710002
5. Żyluk A. The role of genetic factors in carpal tunnel syndrome etiology: A review. Adv Clin Exp Med. 2020;29(5):623-628. doi:10.17219/acem/118846
6. Kumar P, Stiernborg M, Fogdell-Hahn A, et al. Physical exercise is associated with a reduction in plasma levels of fractalkine, TGF-β1, eotaxin-1 and IL-6 in younger adults with mobility disability. PLoS One. 2022;17(2):e0263173. Published 2022 Feb 3. doi:10.1371/journal.pone.0263173
7. Yamanaka Y, Gingery A, Oki G, Yang TH, Zhao C, Amadio PC. Effect of a monocyte chemoattractant protein-1 synthesis inhibitor on fibroblasts from patients with carpal tunnel syndrome. J Orthop Sci. 2021;26(2):295-299. doi:10.1016/j.jos.2020.03.010
8. Yamanaka Y, Gingery A, Oki G, Yang TH, Zhao C, Amadio PC. Blocking fibrotic signaling in fibroblasts from patients with carpal tunnel syndrome. J Cell Physiol. 2018;233(3):2067-2074. doi:10.1002/jcp.25901
9. Genova A, Dix O, Saefan A, Thakur M, Hassan A. Carpal Tunnel Syndrome: A Review of Literature. Cureus. 2020;12(3):e7333. Published 2020 Mar 19. doi:10.7759/cureus.7333
10. Sharma D, Jaggi AS, Bali A. Clinical evidence and mechanisms of growth factors in idiopathic and diabetes-induced carpal tunnel syndrome. Eur J Pharmacol. 2018;837:156-163. doi:10.1016/j.ejphar.2018.08.017
11. Tiwari M. The role of serratiopeptidase in the resolution of inflammation. Asian J Pharm Sci. 2017;12(3):209-215. doi:10.1016/j.ajps.2017.01.003
12. Chammas M, Boretto J, Burmann LM, Ramos RM, Dos Santos Neto FC, Silva JB. Carpal tunnel syndrome – Part I (anatomy, physiology, etiology and diagnosis). Rev Bras Ortop. 2014;49(5):429-436. Published 2014 Aug 20. doi:10.1016/j.rboe.2014.08.001