21/08/2025
Just published 🔥
Chronic Tendinopathy Driven by Neoinnervation: The Role of the Paratenon, Upregulated Neural Biomarkers, and Evolving Evidence – A Scoping Review
🦶Tendinopathy has traditionally been linked to mechanical overload and degenerative changes (Millar et al., 2021; Abate et al., 2009). More recent evidence suggests that neurobiological mechanisms—particularly neoinnervation from the paratenon—play a key role in chronic tendon pain (Ackermann, 2013; Spang et al., 2022). The paratenon, a vascularized connective tissue enveloping the tendon, facilitates gliding and serves as a site for nociceptive signaling and nerve sprouting (Hackett et al., 2016).
📘 A brand-new scoping review by Palee and colleagues (https://pubmed.ncbi.nlm.nih.gov/40773634/ ) systematically evaluates evidence for neoinnervation (nerve ingrowth) in chronic tendinopathy, with emphasis on neural biomarker upregulation and the role of the paratenon. The work follows the PRISMA-ScR framework (Tricco et al., 2018), analyzing 26 studies (21 human, 5 animal) published between 2001 and 2022.
📋 Methods
▶️ The authors conducted a comprehensive search of PubMed, Embase, Web of Science, and Scopus up to June 2024, including clinical human case-control studies and in vivo animal models assessing neoinnervation in tendinopathy. Extracted data included study design, tendon site, biomarker detection methods, neural biomarker status, and paratenon involvement.
🔑 Key Findings
✅ Prevalence of Neoinnervation: 73% (19/26) of studies demonstrated neoinnervation in chronic tendinopathy (Schubert et al., 2005; Lian et al., 2006; Schizas et al., 2012).
✅ Paratenon Role: 76.9% (20/26) implicated the paratenon in nociception and nerve ingrowth, with 53.8% studying both phenomena together (Andersson et al., 2007; Xu et al., 2018).
✅ Biomarker Upregulation:
➡️ PGP 9.5: upregulated in 15 studies; general marker for nerve fibers (Danielson et al., 2006).
➡️ Substance P (SP): upregulated in 13 studies; mediates neurogenic inflammation and pain (Oh et al., 2020; Ackermann et al., 2023).
➡️ CGRP: identified in 9 studies; associated with nociception and vasodilation (Lian et al., 2006).
➡️ Tyrosine Hydroxylase: upregulated in 6 studies, indicating sympathetic innervation (Danielson et al., 2007).
➡️ Other markers included GAP-43 (nerve regeneration), NMDAR1, glutamate, NK1R, adrenoreceptors, neuropeptide Y, chemokines (CCL2, CCL5, CXCL10), and immune cells (macrophages, mast cells, T cells).
➡️ Temporal Trends: Early research (2001–2010) concentrated on PGP 9.5 and SP; later work expanded to CGRP, NMDAR, and immune markers, reflecting a shift toward neuro-immune mechanisms.
🩺 Mechanistic Insights
Neoinnervation and angiogenesis act synergistically in tendon healing but may also perpetuate chronic pain via prolonged nociceptive signaling. SP and CGRP are particularly important for their dual roles in tissue repair and neurogenic inflammation (Scott & Bahr, 2009). The paratenon emerges as a hub for these processes, integrating neural, vascular, and immune pathways.
❓ Therapeutic Implications
Targeting paratenon neoinnervation could offer new strategies for pain relief and tendon repair. Interventions include:
▶️ Minimally invasive paratenon stripping (Naidu et al., 2009).
▶️ Sclerosing injections with polidocanol (Alfredson & Ohberg, 2005).
▶️ High-volume image-guided injections (Chan et al., 2008).
▶️ Ultrasound-guided tenotomy (Wahezi et al., 2023).
❎ Limitations and Research Gaps
Most included studies were case-control or experimental models, with limited longitudinal data. The temporal dynamics of biomarker expression and neoinnervation during disease progression remain poorly characterized. High-quality randomized trials are needed to validate targeted neurobiological interventions.
💡 Conclusion
Chronic tendinopathy involves a complex interplay between neoinnervation, paratenon-mediated nociception, and neuro-immune signaling. Upregulated biomarkers such as PGP 9.5, SP, and CGRP are central to these processes. Therapeutic strategies targeting specific nerve ingrowth pathways in the paratenon hold promise for improving pain management and tendon healing.
📷 Illustration: Schematic showing the pathological nerve ingrowth after tendon injury (https://pubmed.ncbi.nlm.nih.gov/39028489/).
________________________________________
📖 References
Millar NL, Silbernagel KG, Thorborg K, et al. Tendinopathy. Nat Rev Dis Primers. 2021;7:1–21.
Abate M, Silbernagel KG, Siljeholm C, et al. Pathogenesis of tendinopathies: Inflammation or degeneration? Arthritis Res Ther. 2009;11:235.
Ackermann PW. Neuronal regulation of tendon homoeostasis. Int J Exp Pathol. 2013;94:271–286.
Spang C, Masci L, Alfredson H. Is the superficial peritendinous tissue an additional pain driver in patellar tendinopathy? Medicina (Kaunas). 2022;58:601.
Hackett L, Millar NL, Lam P, Murrell GAC. Are the symptoms of calcific tendinitis due to neoinnervation and/or neovascularization? J Bone Joint Surg Am. 2016;98:186–192.
Schubert TEO, Weidler C, Lerch K, et al. Achilles tendinosis is associated with sprouting of substance P positive nerve fibres. Ann Rheum Dis. 2005;64:1083–1086.
Lian Ø, Dahl J, Ackermann PW, et al. Pronociceptive and antinociceptive neuromediators in patellar tendinopathy. Am J Sports Med. 2006;34:1801–1808.
Schizas N, Weiss R, Lian Ø, et al. Glutamate receptors in tendinopathic patients. J Orthop Res. 2012;30:1447–1452.
Danielson P, Alfredson H, Forsgren S. Distribution of general (PGP 9.5) and sensory (substance P/CGRP) innervations in the human patellar tendon. Knee Surg Sports Traumatol Arthrosc. 2006;14:125–132.
Oh SY, Kim DK, Han SH, et al. Sustained exposure of substance P causes tendinopathy. Int J Mol Sci. 2020;21:8633.
Scott A, Bahr R. Neuropeptides in tendinopathy. Front Biosci (Landmark Ed). 2009;14:2203–2211.
Naidu V, Abbassian A, Nielsen D, et al. Minimally invasive paratenon release for non-insertional Achilles tendinopathy. Foot Ankle Int. 2009;30:680–685.
Alfredson H, Ohberg L. Sclerosing injections to areas of neovascularisation reduce pain in chronic Achilles tendinopathy. Knee Surg Sports Traumatol Arthrosc. 2005;13:338–344.
Chan O, O’Dowd D, Padhiar N, et al. High volume image guided injections in chronic Achilles tendinopathy. Disabil Rehabil. 2008;30:1697–1708.
Wahezi SE, Patel A, Yerra S, et al. Percutaneous ultrasound-guided tenotomy for trochanteric pain syndrome: One-year durability results. Pain Physician. 2023;26:393–401
