Biology of Tendinopathy

“Let’s be very honest here, we really haven’t advanced treatments in this condition compared to our musculoskeletal colleagues in osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, pick it. We’re crap at treating this disease and we’ve probably been that way because we haven’t paid enough attention to the biology…”

This is a rather bold statement from that many of us probably would not like to acknowledge. Anyone reading this newsletter (or taking it a step further and consuming the Summit presentations) has likely spent incalculable hours attempting to stay current and add layers of nuance to their approaches. But if we’re honest with ourselves, how different are our treatment plans, training programs, or medical advice compared to a decade ago?

This is not meant to be a knock on any individual; rather, it is a reflection of our collective lack of perspective when tackling the problem of tendinopathy.

Neal Millar does an excellent job addressing this efficiently and pointedly in his presentation to the Tendon Summit. He makes the point that while load is a main driver of pathophysiology, it is not the *only* aspect that matters. He highlights the many contributors (such as environmental elements, pharmacological history, genetics, etc.) and their interacting effects on the progression of the condition.

From there, Millar shifts the focus toward the molecular-level biology that underpins these clinical presentations, particularly the inflammatory pathways that shape tendon homeostasis.

Historically, the concept of inflammation in tendinopathy has been contentious. In fact, the terminology we use to describe the pathology reflects our shift away from recognizing its importance- with the sentiment being: “there is no clinical evidence of a classic inflammatory event in tendinopathy and that a chronic degenerative disorder devoid of an inflammatory process prevails.” [1]

This historical skepticism makes Millar’s work even more important. He outlines the compartments of inflammatory mechanisms that regulate tendon homeostasis and shows how these pathways are not peripheral to tendinopathy but central to its onset and progression. [1,2]

Cytokine signaling, immune cell involvement and stromal activation are now recognized across the full spectrum of tendinopathy, including early elevations in IL‑17 family cytokines that shift tenocytes toward a type III collagen phenotype. This updated understanding shows that mechanical load does not act in isolation but triggers inflammatory signaling that influences how tendon cells remodel their matrix. These biological responses shape whether tissue becomes more organized or more disorganized over time, which in turn affects symptom progression and recovery. [1]

Importantly, this pursuit is more than simply expanding our knowledge base; it is uncovering previously unexplored points of intervention. Millar’s own work illustrates this clearly: his group’s Phase 1 trial of miR‑29a replacement (TenoMiR) in lateral elbow tendinopathy demonstrated that precise manipulation of post‑transcriptional regulators can meaningfully alter tendon structure and symptoms. [6]

Building on this foundation, Millar uses his presentation to walk through two forthcoming studies that push this direction even further. One targets inflammatory‑protein signaling and the other advances microRNA‑based therapy, each offering a concrete example of how tendon biology can be leveraged for targeted intervention. Rather than speculative concepts, these projects represent the leading edge of where tendon therapeutics are moving. The field is shifting toward biologically informed interventions that act on the mechanisms driving tendon disease.

Why This Matters For Clinicians

As hands-on practitioners, it may be hard to appreciate the applicability of these findings. The majority of us will not be the ones prescribing medication or performing injections- much less experimenting with molecular pharmacology. However, it remains important to stay up to date on this line of thinking for several reasons.

Indirectly:

If we want to be considered true subject matter experts, and trusted primary points of contact for those managing this condition, we must know the full breadth of treatment options available. That includes understanding not only what these emerging interventions are, but also the contextual factors that moderate their success. This knowledge allows us to guide patients, collaborate with medical colleagues, and interpret new evidence with a level of nuance that reflects the complexity of tendon disease.

Directly:

Although emerging work in exercise immunology, systems immunology, and cytokine profiling clearly demonstrates that physical activity can modulate inflammatory signaling, immune cell dynamics, and tissue‑level recovery processes, these findings remain largely disconnected from the specific mechanical and clinical questions that matter in tendinopathy. Current research establishes that exercise intensity, chronic training status, metabolic availability, and recovery behaviors influence cytokine expression and immune regulation, yet none of these studies interrogate how exercise variables themselves (load magnitude, frequency, time‑under‑tension, muscle–tendon length, repetition schemes, etc.) alter these pathways in a pathological tendon. As a result, the literature provides strong evidence that exercise influences systemic and local inflammatory biology, but it does not tell us whether the variables clinicians manipulate every day meaningfully shift these processes in tendinopathic tissue. [3,4,5]

This gap is critical: without mechanistic data linking specific loading parameters to specific biological responses in tendon pathology, clinicians are left extrapolating from healthy‑tissue models, whole‑body cytokine responses, or athlete‑adaptation studies that do not reflect the altered cellular, metabolic, and neuroimmune environment of a symptomatic tendon.

These findings point toward an emerging direction in the literature: a future in which exercise–immune interactions are examined not just globally, but in relation to the specific loading variables clinicians manipulate in practice. While that work does not yet exist for tendinopathy, the trajectory of current research suggests it will become increasingly relevant.

For clinicians, staying aware of these developments is less about changing practice today and more about remaining positioned at the forefront of how exercise variables may eventually be linked to tissue‑specific biological responses.

In The Recordings

This newsletter covers the framework but the recording gives meaning to the biology behind it in full. This includes more expansive looks at the work alluded to by Millar's group targeting inflammatory-protein signaling and microRNA-based therapy as well as discussions around the role of the enthesis, important cell to cell interactions, and other molecular targets for future treatments. If that's the direction the field is moving, this is the earliest look at where it's headed.

Time is a finite resource, and it is a near‑impossible task to devote the necessary attention to all aspects pushing the field forward. Our goal with the Tendon Summit Insider is to help curate and streamline this process for working professionals. We will continue to highlight important emerging research and trends, but we also encourage readers to take advantage of the depth offered by our presenters. Their expertise provides an opportunity to engage with these topics at a level that is difficult to achieve through passive reading alone, and to build the kind of conceptual fluency that strengthens clinical reasoning and supports better decision making in day‑to‑day practice.

Next up, we review the presentation of Falk Mersmann — personalized strain-based loading, muscle-tendon imbalance, and what it actually means to prescribe load with precision.

This will go out in two weeks!

Debrief written by: Jason Eure, PT, DPT, OCS, CSCS

Reference List

1. Millar, N., Murrell, G. & McInnes, I. Inflammatory mechanisms in tendinopathy – towards translation. Nat Rev Rheumatol 13, 110–122 (2017). https://doi.org/10.1038/nrrheum.2016.213.

2. Millar NL, Dean BJ, Dakin SG. Inflammation and the continuum model: time to acknowledge the molecular era of tendinopathy. Br J Sports Med 2016.

3. Cook CE, Keter D, Cade WT, Winkelstein BA and Reed WR.Manual therapy and exercise effects on inflammatory cytokines: a narrative overview. Front. Rehabil. Sci. 2024.5:1305925. doi: 10.3389/fresc.2024.1305925

4. Reitzner SM, Brodin P. The Immune System as a Biosensor of Health and Athletic Performance. Scand J Med Sci Sports. 2026 Mar;36(3):e70258. doi: 10.1111/sms.70258. PMID: 41842715; PMCID: PMC12994555.

5. Małkowska P, Tomasiak P, Tkacz M, Zgutka K, Lubkowska A, Buryta R, Rosiński Ł, Maciejewska-Skrendo A, Proia P, Tarnowski M. Differential Inflammatory Response to Exhaustive Exercise in Trained and Untrained Individuals: Potential Biomarkers of Training Adaptation. Applied Sciences. 2026; 16(6):2643. https://doi.org/10.3390/app16062643

6. Millar, N., Donnelly I, McInnes I., Ball D., Leung PM., Kirwadi A., Gilchrist DS. First in Human study of a microRNA29a mimic (TenoMiR) in patients with lateral elbow tendinopathy - a randomised, Placebo Controlled Phase 1 trial. medRxiv 2025.08.23.25332854; doi: https://doi.org/10.1101/2025.08.23.25332854