Beyond local injury: pathogenic roles of metabolic, endocrine, and aging-associated systemic factors in tendinopathy and novel therapeutic strategies

Abstract

Tendinopathy, characterized by persistent pain and impaired function, is a globally prevalent condition imposing heavy socioeconomic burdens. Long regarded as an isolated local lesion, it is increasingly recognized as a regional manifestation of systemic dysregulation driven by the metabolic-endocrine-aging axis—not merely a peripheral “background factor.” This review systematically analyzes four key pathogenic pathways: hyperglycemia-induced advanced glycation end-product (AGE) deposition, dyslipidemia-driven metabolic inflammation, sex hormone fluctuation-mediated collagen homeostasis disruption, and the cellular senescence-senescence-associated secretory phenotype (SASP) cascade. Together, these systemic factors remodel the tendon cell microenvironment, alter extracellular matrix biomechanics, and reduce the tissue’s mechanical load tolerance. Traditional local-focused treatments have demonstrated limited efficacy, requiring a shift to a “systemic-local synergistic regulation” paradigm. Critically, a new clinical staging system integrating systemic risk factors is urgently needed. By establishing a “systemic-local” crosstalk model and highlighting the urgent need for a novel clinical staging system integrating systemic risk factors—our primary novel contribution—this review provides key insights for researchers and clinicians, supporting the optimization of personalized therapeutic strategies and improved clinical outcomes for tendinopathy.

Introduction

Tendinopathy refers to persistent tendon pain and loss of tendon function induced by repetitive mechanical loading, which is characterized by pain, impaired function, and reduced exercise tolerance [1]. Epidemiological evidence across nations indicates that the prevalence of tendinopathy has been on a steady upward trend over the past decades, impacting professional athletes, amateur enthusiasts, and individuals of all age groups alike. This uptick is partly attributed to a growing elderly demographic [2] and increased population activity levels [3]. An EU report focusing on the progression of occupational diseases related to specific musculoskeletal disorders supports these findings by revealing that the incidence of tenosynovitis and enthesopathies rose by approximately 10% to 20% between 2013 and 2019. Studies have indicated that tendinopathy in the lower extremities is associated with an incidence of up to 10.52 cases per thousand individuals [4]. In the majority of tendinopathy cases [3], the pathology is associated with overuse [5], leading to multiple overlapping pathological processes that result in pain, diffuse or local swelling, loss of tissue integrity, and motor dysfunction. The tendons most commonly affected by overuse include the rotator cuff tendons, patellar tendon, gluteal tendons, and Achilles tendon, among others [1, 3, 6].

The aetiopathogenesis of tendinopathy remains incompletely understood. Among the most prominent etiological factors of tendinopathy are tendon overuse and excessive mechanical loading [7], yet they are also linked to specific sports—particularly explosive sports (e.g., jumping, sprinting)—training-related errors [8] (pertaining to intensity, frequency, and technical execution), suboptimal training venues, unfavorable weather conditions, and ill-fitted footwear or sports equipment [9]. Nevertheless, constitutional and systemic factors—including sex [10], aging [7], obesity (OB) [11], smoking [12], the use of corticosteroids and statins [13], and psychological factors such as anxiety and self-efficacy [14]—also appear to contribute to the pathogenesis of this condition (Fig. 1).

Fig. 1.

Systemic factors directly driving tendinopathy: the metabolic-endocrine-aging axis. The diagram illustrates the core pathogenic logic of tendinopathy: systemic factors including diabetes (hyperglycemia-induced AGEs deposition), obesity (adipokine imbalance and metabolic inflammation), estrogen fluctuation (collagen homeostasis disruption), and aging (cellular senescence and SASP release) directly act on local tendon components, disrupting the tendon’s physiological state and biomechanical properties, which ultimately lowers the tendon’s mechanical load threshold and leads to tendinopathy, embodying the core hypothesis that tendinopathy is a regional manifestation of systemic disorders

Studies have confirmed that the prevalence of tendinopathy shows an upward trend with advancing age, and females—particularly postmenopausal women—have a higher susceptibility to tendinopathy than males [3]. This sex-specific difference is partially driven by the metabolic interplay between estrogen decline, adiposity-related metaflammation, and disrupted collagen homeostasis, a mechanistic cascade that is elaborated in detail in the subsequent section on sex hormone fluctuation-mediated endocrine dysregulation [15, 16].

Among a subset of patients, metabolic factors—such as obesity, hypercholesterolemia, and diabetes mellitus—have been demonstrated to influence the incidence and severity of tendinopathy [3]. High-quality evidence including systematic reviews, meta-analyses and multicenter epidemiological studies have established a robust correlation between tendinopathy and type 2 diabetes (T2D) [17–20], conferring an elevated risk of tendon pain, tendon rupture, and poorer post-repair outcomes in patients with T2D. Furthermore, subsequent immobilization resulting from tendon pathology exerts a significant influence on diabetes management through diminished physical activity and compromised quality of life.

Similarly, hypercholesterolaemia may accumulate in tendons, resulting in tendon xanthoma in severe instances [21]. Additional health disorders linked to tendinopathy encompass obesity, hypertension, hypercalcaemia, dyslipidaemias, haemochromatosis, endocrinopathies (e.g., thyroid disease, Cushing syndrome, hypogonadism, and menopause), rheumatoid disease, gout, pseudogout, heritable connective tissue diseases, psoriasis, and spondyloarthropathies, among others [22].

Tendinopathy rehabilitation encompasses a diverse range of strategies, broadly classified into two main modalities: passive and active interventions. Passive interventions comprise pharmacotherapeutic agents [23], injection-based therapies [24, 25], orthotic devices [26], extracorporeal shock wave therapy (ESWT) [27], therapeutic ultrasound [28], and low-level laser therapy [29]. Conversely, active strategies involve tendon loading exercises [30], patient education, and individualized load management [31]. Surgical intervention is indicated when conservative (non-surgical) treatments for tendinopathy prove ineffective. Despite the wide spectrum of treatment options available, the efficacy of tendinopathy interventions remains suboptimal [23]. A subset of patients continues to suffer from persistent pain post-treatment, which severely impairs their quality of life and imposes considerable socioeconomic burdens [3].

Currently, there is a paucity of comprehensive summaries on the impacts of systemic factors on tendinopathy and associated therapeutic strategies. Tendon injury and tendinopathy involve impaired natural healing and defective extracellular matrix remodeling, with healed tissue unable to restore the biomechanical integrity and function of native tendon [32]; this well-recognized repair limitation is a core focus of classical tendinopathy research, yet the key role of systemic metabolic, endocrine and aging-related dysregulation in exacerbating this intrinsic defect remains poorly summarized and elucidated. Against this backdrop, emerging evidence suggests the core hypothesis of this review: the systemic metabolic-endocrine-aging state is not a “background factor” of tendinopathy, but rather a critical susceptibility modifier. Through multiple well-established pathways—including chronic hyperglycemia-induced deposition of advanced glycation end-products (AGEs), lipid abnormalities triggering lipotoxicity and inflammation, sex hormone fluctuations disrupting collagen homeostasis, and cellular senescence establishing a toxic microenvironment—it fundamentally alters the survival microenvironment of tenocytes, remodels the biomechanical properties of the extracellular matrix (ECM), and impairs the tendon’s injury repair capacity [33], ultimately leading to a significant reduction in the tendon’s “mechanical load threshold” and increased susceptibility to degeneration. This renders previously tolerable normal physiological loads sufficient to induce pathological degeneration of the tendon. As a critical susceptibility modifier for tendinopathy, this systemic state constitutes a key pathological mechanism that traditional local treatments fail to adequately address.

To validate this hypothesis, this review will systematically elaborate on four core pillars: first, the metabolic disorder axis mediated by hyperglycemia and AGEs; second, tendon homeostasis imbalance induced by lipid abnormalities; third, the critical regulatory role of sex hormone fluctuations; and fourth, the toxic effects of cellular senescence and SASP. By integrating epidemiological, molecular mechanistic, and clinical translational evidence, we aim to establish a novel “systemic-local” crosstalk model of tendinopathy pathogenesis, thereby assisting researchers and clinicians in tailoring optimal future therapeutic strategies.

Survey methodology

This review is a narrative review with a systematic literature search strategy, conducted by retrieving relevant English-language literature from the PubMed (https://pubmed.ncbi.nlm.nih.gov) and Web of Science (https://www.webofscience.com/wos) databases. We searched for English-language articles published prior to November 30, 2025, using the key terms: “(tendinopathy) AND (metabolic-endocrine-aging axis OR hyperglycemia OR dyslipidemia OR sex hormone fluctuations OR cellular senescence OR clinical management)”. Eligibility assessment was conducted through reviewing titles, abstracts, and full texts to ensure relevance to the core pathogenic mechanisms or clinical management of tendinopathy driven by the metabolic-endocrine-aging axis. Additional references were identified by hand-searching the reference lists of included studies. Finally, a total of 192 publications were included in this review. The included literature was classified into four core themes: metabolic disorder-associated pathogenic mechanisms of tendinopathy, sex hormone-mediated tendon homeostasis imbalance, cellular senescence-SASP cascade-related mechanisms in tendinopathy, and novel clinical management strategies targeting systemic factors. As this work is designed as a narrative review (rather than a systematic review/meta-analysis), PRISMA guidelines and PROSPERO registration—standards for systematic reviews—were not applied in the present study.

To clarify the scope of literature included in this narrative review, the key criteria applied during title/abstract and full-text screening for study inclusion and exclusion are summarized as follows: (1) Peer-reviewed English articles published on or before November 30, 2025 were included, while non-English articles without available translations, conference abstracts, case reports, letters to the editor, and unpublished preprints/theses were excluded; (2) Studies investigating the pathogenic mechanisms, clinical manifestations, or therapeutic strategies of tendinopathy associated with metabolic, endocrine, and aging-related systemic factors were included, whereas research unrelated to the metabolic-endocrine-aging axis and tendinopathy crosstalk was excluded; (3) In vitro, in vivo, clinical observational, and review studies with complete methodological and result descriptions were included, and studies focusing solely on acute traumatic tendon injuries without linkage to metabolic-endocrine-aging systemic factors were excluded.

To ensure the reliability of the synthesized evidence and address potential methodological bias, a targeted quality assessment of the 192 included studies was conducted according to their research types, with classic bias assessment tools as the reference framework: SYRCLE’s Risk of Bias tool for animal studies, ROBINS-I for clinical observational studies, and Cochrane RoB 2 for randomized controlled trials (RCTs). For in vitro cell studies, quality evaluation was based on experimental design rigor (e.g., presence of blank/positive controls, sample size, technical repeatability). In the literature screening process, we prioritized including high-quality studies with well-designed experimental protocols, sufficient sample sizes, detailed methodological descriptions, and reproducible results; low-quality studies with critical flaws (e.g., no control groups, excessively small sample sizes, ambiguous experimental design, and unvalidated results) were strictly excluded. Overall, the included studies were predominantly of moderate to high methodological quality, and a small number of low-quality studies were only used as supplementary evidence for preliminary mechanistic exploration, without being involved in the derivation of core conclusions of this review.

In addition to the above literature retrieval, classification, and quality assessment processes, we systematically verified the methodological rigor of key primary studies supporting the core conclusions of this review. Specifically, we confirmed that all cited foundational studies (e.g., those investigating pathogenic mechanisms or clinical interventions) have reported critical measurement device specifications (e.g., manufacturer, model) and relevant validation references, ensuring the reliability of the synthesized evidence. This verification aligns with the manuscript’s focus on stronger synthesis and conceptual integration, further reinforcing the rigor of the review’s evidence base.

The hyperglycemia-advanced glycation end-products pathogenic axis

Numerous studies have documented an elevated incidence of tendinopathy in patients with T2D, and this epidemiological link has been validated by multiple meta-analyses—all confirming that individuals with T2D face a heightened risk of developing tendinopathy [34]. Notably, this association may be further strengthened when accounting for factors such as age, ethnicity, duration of T2D, glycated haemoglobin (HbA1c) levels, and body mass index (BMI) in affected individuals [35]. Overall, compared to non-T2D individuals, patients with T2D typically present with more severe tendinopathic manifestations [36], accompanied by intensified tendon pain [37], and inherently carry a higher risk of tendon rupture that necessitates hospitalization [38]. The most prevalent types of tendinopathy in T2D patients include Achilles tendinopathy (AT), rotator cuff disease, and flexor tendinopathy of the hand and fingers [39].

Diabetic tendons exhibit a spectrum of pathological alterations. Macroscopically, a distinct loss of the intact tendon’s characteristic glistening white appearance is commonly observed, accompanied by increased swelling, expanded volume, augmented thickness, and heightened stiffness [40]. At the microscopic level, key features include focal collagen degeneration—manifested as smaller, disorganized fibrils with abnormal packing—alongside reduced elastin fiber content and diminished cellularity [34, 37]. In animal models of supraspinatus, patellar, and Achilles tendinopathy, diabetic tendons exhibited adverse responses to mechanical stress and displayed perturbations in both micro- and nanostructures when compared to tendons from healthy littermates [41, 42]. Furthermore, diabetic obese mice demonstrated impaired tendon repair following injury, which was reflected in poorer biomechanical performance relative to non-diabetic animals [43].

Numerous studies have been conducted to examine the causal roles of individual metabolic factors associated with T2D in the pathogenesis of tendinopathy. Specifically, chronic hyperglycaemia, AGEs, obesity (OB), and insulin resistance have all been identified as key contributors to the development of diabetic tendinopathy, acting both individually and synergistically.

Several in vitro studies have explored the impact of hyperglycaemia on tendon cells. For instance, Tsai et al. demonstrated in an in vitro experiment that high glucose concentrations markedly upregulated the expression of matrix metalloproteinase-9 (MMP-9) and matrix metalloproteinase-13 (MMP-13) in rat Achilles tendon cells [44]. Likewise, Ueda and co-workers reported elevated levels of MMP-2, interleukin-6 (IL-6), tissue inhibitors of matrix metalloproteinases-1 and − 2 (TIMP-1/2), NADPH oxidase-4 (NOX4), and type III collagen in tendon cells cultured under high-glucose conditions [45]. Additionally, these cells exhibited significantly increased reactive oxygen species (ROS) production, accompanied by reduced type I collagen expression and impaired cell proliferation [45].

Poulsen et al. also documented alterations in the oxidative microenvironment: they found that high glucose triggered apoptosis in human tendon cells following acute exposure to oxidative stress (100 mmol/L H₂O₂ for 18 h) [46]. In contrast, cells cultured in a low-glucose environment remained fully viable after H₂O₂ treatment and even showed enhanced expression of type I collagen, SOX9, and scleraxis [46]. Collectively, these findings indicate that hyperglycaemia may disrupt tendon cell homeostasis by lowering the threshold for tolerance to stressful stimuli, shifting cellular responses from adaptive to degenerative [47]. Moreover, hyperglycaemia may directly perturb the redox balance by altering the polyol pathway, ultimately leading to cellular oedema [47].

Another potential mechanism is the downregulation of the adenosine monophosphate-activated protein kinase (AMPK)/early growth response factor 1 (Egr1) pathway: Wu et al. showed that high glucose exposure significantly reduced the expression of scleraxis, mohawk (MKX), type I collagen, biglycan, transforming growth factor-β1 (TGF-β1), and Egr1 in human tenocytes [48]. Blocking Egr1 activity with small interfering RNA (siRNA) and AMPK activity with Compound C yielded similar results, highlighting the central role of these pathways in the molecular cascades underlying diabetic tendinopathy [48].

Hyperglycaemia may also impair tendon healing by disrupting the behavior of local stem cells when exposed to glucose. Lin et al. showed that culturing patellar tendon-derived stem cells (TDSCs) in a high-glucose medium led to increased apoptosis, impaired proliferation, and reduced expression of type I collagen and tendon cell markers [49]. Similarly, Kwan et al. isolated TDSCs from tendinopathic and healthy human tissue samples and subjected them to interleukin-1β (IL-1β), high glucose, or a combination of both [50]. High glucose elevated cyclooxygenase-2 (COX-2) levels in both TDSC populations, while tendinopathic TDSCs exhibited downregulated expression of arachidonate lipoxygenase-15 (ALOX15), formyl peptide receptor-1 (FPR1), and chemerin receptor-23 (CMKLR2)—all of which are involved in producing specialized pro-resolving mediators—thereby amplifying the pro-inflammatory response [50].

Beyond high glucose levels, glycaemic variability—defined as fluctuations between hypoglycemic and hyperglycemic states (and vice versa)—has emerged as a key focus of research regarding macro- and microvascular complications in T2D, and may also contribute to the pathogenesis of diabetic tendinopathy [51]. Indeed, preclinical studies have demonstrated that intermittent exposure to glycaemic peaks and nadirs augments oxidative stress and induces endothelial dysfunction [51]. Notably, endothelial dysfunction itself is recognized as a pathophysiological driver of tendinopathy [52].

Chronic hyperglycaemia is directly linked to the accumulation of AGEs, which form via non-enzymatic glycation and oxidation of various proteins and lipids upon exposure to excessive glucose concentrations [53]. Notably, AGE formation is typically irreversible and induces cross-linking of glycated proteins—these proteins ultimately lose their biological activity, trigger oxidative stress, and subsequently cause lipid peroxidation and cell membrane damage [54]. Collagen cross-linking commonly occurs in diabetic tendons, leading to reduced fiber sliding and impaired viscoelasticity, which in turn increase tendon brittleness and stiffness [55]. Under tensile loading, the cross-linked collagen triple helix undergoes local micro-unfolding, thereby increasing the number of proteolytic sites and enhancing vulnerability to collagenase digestion [56]. Cross-linking of the ECM is mediated by several enzymes, including transglutaminase 2 (TG2); in vitro studies have shown that TG2 levels rise in tenocytes following exposure to AGEs [57]. Additionally, TG2 participates in cell-ECM interactions via integrins and may alter the differentiation of patellar TDSCs toward a non-tenogenic phenotype [58]. In a recent study, Lee et al. further demonstrated that AGE-related collagen cross-linking inhibits tendon discrete plasticity—a physiological adaptive mechanism that likely prevents rupture in chronically overloaded tendons by promoting regional collagen kinking [59]. Collectively, these alterations exert a significant impact on tendon structure and function.

Furthermore, AGEs exert diverse biological effects by binding to AGE receptors (RAGE) and toll-like receptors (TLRs) on the cell surface, which activates the MAPK and NF-κB pathways [34] and ultimately drives a catabolic response in tendon tissue. Patel et al. recently reported that rat Achilles tendon cells cultured in AGE-containing medium exhibited reduced proliferation and type I collagen expression, with increased type III collagen expression in a dose-dependent manner [60]. AGEs also significantly decreased mitochondrial ATP synthesis and elevated mitochondrial apoptotic markers and ROS production [60]—these cellular-level impairments directly compromise the energy supply required for tenocyte proliferation, collagen deposition, and extracellular matrix remodeling, leading to delayed tendon repair, poor healing outcomes, and a significantly increased risk of tendon rupture in patients with T2D who accumulate AGEs.

Increased apoptosis induced by AGE accumulation may also affect TDSCs. In an in vitro study, Xu et al. found that apoptosis led to a significant reduction in TDSC viability, which was partially counterbalanced by enhanced cell autophagy accompanied by increased osteogenic differentiation [61]. Notably, TDSC function was rescued by treatment with pioglitazone—a peroxisome proliferator-activated receptor γ (PPARγ) agonist clinically used for T2D management [61]. Pioglitazone enhanced TDSC autophagy, reduced apoptosis and senescence, maintained the tenogenic phenotype, and attenuated ectopic calcifications both in vitro and in vivo [61].

AGEs may also impair tendon vascularization by altering the expression of vascular endothelial growth factor (VEGF) [62]. VEGF-mediated neoangiogenesis and inflammation are critical for promoting capillary growth and augmenting vascular supply to acutely damaged tendons following injury [62]. Ahmed et al. reported a deficiency of VEGF in diabetic rats after AT transection [63]. Thus, reduced VEGF expression post-tendon injury may hinder tendon healing, which is consistent with the higher risk of tendon rupture and impaired healing capacity observed in patients with T2D [39].

Similar to other cell populations, tenocytes are directly engaged in insulin signaling. In fact, these cells consistently express insulin, glucagon, insulin receptors (IRs), and glucose transporter-2, and can secrete insulin in response to glucose stimulation [64].

Additionally, insulin is also implicated in the differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs) toward the tenogenic lineage. Mazzocca et al. exposed BM-MSCs isolated during rotator cuff repair to insulin in an in vitro setting, which led to enhanced expression of tendon-specific markers (i.e., type I and type III collagen, scleraxis, and tenascin C) and the acquisition of an elongated, tendon-like phenotype [65]. Collectively, these findings underscore that insulin is pivotal to tenocyte fate determination, metabolism, and functional activity, and that disruption of insulin signaling in T2D may exert a notable influence on the pathogenesis of diabetic tendinopathy.

The dyslipidemia-mediated tendon homeostasis imbalance pathogenic axis

Obesity has been identified as a risk factor for mechanical alterations in tendons. Specifically, clinical studies show that obese individuals exhibit significantly increased tendon displacement and strain, while preclinical models confirm that high-fat diet exposure increases tendon cross-sectional area and reduces modulus [66].

Obesity contributes to tendinopathy pathogenesis through two distinct mechanisms: mechanical and metabolic mechanisms [67]. Mechanically, excess body weight alters tendon load responsiveness, primarily impacting weight-bearing tendons of the lower extremities [68]. Metabolically, obese individuals secrete over 600 bioactive adipokines—molecules that regulate key biological processes including appetite and satiety, fat distribution, insulin secretion and sensitivity, glucose metabolism, inflammation, vascular growth, and adipocyte function [69–75]. In obesity, expanded adipose tissue exhibits an altered adipokine secretion profile, with elevated proinflammatory factors such as leptin and reduced anti-inflammatory mediators [71, 72, 76]. Hypertrophic adipocyte hypoxia induces apoptosis, macrophage recruitment, and sustained inflammatory signaling [77], leading to a state of low-grade metaflammation [76] accompanied by macrophage phenotypic switching and impaired regulatory T (Treg) cell function and quantity [47, 69, 73, 78–81].

A recent study explored the effects of a high-fat diet (HFD) and apolipoprotein E (ApoE) deficiency on the mechanical properties of the tail tendon. Consistent with expectations, ApoE-deficient mice exhibited significantly higher cholesterolaemia than wild-type mice, while HFD-fed mice showed increased body mass, elevated cholesterol levels, and reduced tendon total modulus compared to control mice on a low-fat diet (LFD) [82]. Overall, tendon healing is compromised in animals fed a HFD compared to those on a LFD. Specifically, HFD is associated with impaired post-surgical tendon recovery, characterized by markedly increased tendon stiffness—far more pronounced than in the LFD group—and reduced metatarsophalangeal (MTP) joint flexion angle shortly after surgery. This functional deficit persists long-term, extending to weeks post-surgery. Similarly, HFD-fed animals exhibit significantly higher tendon gliding resistance than LFD-fed counterparts over time. Macroscopic structural abnormalities in the HFD group also lead to compromised mechanical performance, including lower energy required to reach maximum force and a less pronounced increase in maximum failure load [83, 84].

Furthermore, histological analyses post-surgery revealed additional disparities: at 14 and 28 days, HFD-fed mice exhibited a smaller repair tissue area, reduced cellularity, and diminished collagen remodeling with poorer fiber alignment [43]. By day 28, the HFD group also showed more severe tendon adhesions, while the LFD group displayed distinct spacing at the repair site [83]. A HFD induces substantial histological alterations in tendons regardless of surgical intervention. Tendon repair tissue volume is diminished in HFD-fed mice, and tendon healing efficacy is compromised due to persistent adhesions. Even in the absence of surgery or trauma, tendons from HFD-fed mice exhibit reduced fibril diameter and distinct histological composition—characterized by elevated glycosaminoglycan (GAG) and hydroxyproline levels [66], as well as increased fat infiltration and cell density. Notable disparities in tissue repair were observed post-surgery: compared with LFD-fed mice, HFD-fed mice showed a significant reduction in repair tissue area, decreased cell density, and impaired collagen remodeling with poorer fiber alignment [43]. HFD-fed mice exhibited inferior tendon healing efficacy: adhesions between the tendon and surrounding soft tissues persisted at 28 days post-repair in the HFD group but were absent in the LFD group, accompanied by a notably robust granulation tissue response [83]. Consistent with non-surgical observations, fibril diameter was significantly smaller in HFD-fed mice than in LFD-fed mice [84]. Additionally, obese rats fed an HFD demonstrated elevated tendon hydroxyproline levels [66], along with increased GAG content, fat infiltration, and hypercellularity [85]. The metabolic mechanism of obesity-induced tendon homeostasis imbalance is a preliminarily confirmed mechanism, supported by high-fat diet animal models but lacking clinical evidence from weight loss interventional studies in tendinopathy patients.

The sex hormone fluctuation-mediated endocrine dysregulation pathogenic axis

Accumulating evidence indicates that estrogen status modulates tendon matrix homeostasis, and influences tendon susceptibility to chronic degenerative changes under mechanical loading or metabolic stress—though its role as a direct driver of degenerative tendinopathy remains insufficiently supported by current research [16, 86–88]. Previous investigations have shown that rats with estrogen deficiency induced by ovariectomy or other methods exhibited a significant reduction in tenocyte migration, healing, and proliferation upon anatomical examination following routine repair [16, 86, 87], along with a decrease in tendon stiffness and tensile strength [87, 88]. A wealth of research has confirmed that estrogen holds a certain correlation with tendinopathy [15, 89–91]. Epidemiological studies have shown that female patients with estrogen deficiency have a 48.00% higher incidence of rotator cuff tendon injury than those without estrogen deficiency [92]. A study by Kesikburun S et al. demonstrated that the prevalence of wrist pain during pregnancy is approximately 33.20% [93], and among the causes of distal upper extremity pain in pregnant women, stenosing tenosynovitis predominates. This condition mainly occurs after the 5th month of pregnancy and is more common in patients over 30 years old; some scholars suggest that this may be associated with hormonal changes during pregnancy. Furthermore, several studies on the role of estrogen in tendon biology have indicated that women have a higher risk of developing tendinopathy, and the risk varies according to premenopausal and postmenopausal status as well as different phases of the menstrual cycle, rather than being solely attributable to aging [94].

Estrogens are classified into two categories: animal estrogens and phytoestrogens, each with multiple subtypes. Phytoestrogens are compounds with biological activities similar to animal estrogens, structural similarity to those in mammals, and weak estrogenic effects [95]. Genistein is a plant-derived isoflavone phytoestrogen naturally present in soybeans [96]. Carroll et al. [97], through a study on the effect of genistein on tendons in estrogen-deficient rats, found that genistein can prevent collagen loss during estrogen deficiency, improve tendon function in estrogen-deficient rats, and enhance tendon stress response. However, its mechanism of improving tendon injury does not involve collagen remodeling, but mainly acts on genes related to cell proliferation.

In addition to phytoestrogens, animal estrogens have also been confirmed to affect tendon functional characteristics. Animal estrogens are a class of steroid compounds with extensive biological activities secreted by the ovaries. 17β-estradiol (E2) is an animal estrogen; in a study where E2 was used to treat masticatory muscle tendon cells in mice, tendon hyperplasia was observed. This also confirms that E2 can promote the expression of genes related to cell proliferation and facilitate tenocyte differentiation [98]. Furthermore, in several studies investigating the effect of oral contraceptives containing ethinylestradiol on adaptation to resistance training, compared with the control group, the combined effect of estrogen supplementation and exercise increased the synthesis efficiency of collagen fibers, while tendon collagen turnover was slower in oral contraceptive users [99–101]. This indicates that estradiol enhances tendon collagen synthesis and overall tendon collagen turnover, which helps maintain tendon stability and repair tendon injuries.

In summary, numerous studies on the effect of different types of estrogens on tendon injury have found that estrogens play a beneficial role in tendon repair. In vivo studies have shown that estrogens can promote tendon anabolism. In vitro experiments have also confirmed that various estrogens can promote tenocyte proliferation, increase tendon stiffness, tensile strength, and stress.

Estrogen receptors (ERs) are a class of protein molecules, with classical nuclear receptors being estrogen receptor α (ERα) and estrogen receptor β (ERβ). Even the same hormone can elicit distinct or even opposite biological effects when binding to different receptors [90]. Studies have observed overexpression of ERβ in tenocytes and synovial tissue of postmenopausal women with carpal tunnel syndrome [102, 103], confirming that in tendinopathy, estrogen is likely to promote inflammation and angiogenesis by inducing ERβ overexpression, thereby accelerating the inflammatory process. In research on posterior tibial tendon dysfunction, both ERα and ERβ were detected in normal and pathological tendons of both male and female patients [104, 105]. Furthermore, studies on torn supraspinatus tendons and tenocyte nuclei from both genders revealed that ERβ expression was significantly higher in postmenopausal female samples compared to male samples [90, 106]. In contrast, there was no significant difference in ERα expression between males and females, which further confirms the functional role of ERβ in tendinopathy and indirectly indicates that ERα does not play a dominant role in the pathogenesis of tendinopathy. Additionally, Deghan et al. [107, 108] demonstrated in their study on ERα- and ERβ-mediated relaxin receptor expression that ERβ overexpression upregulates relaxin receptor expression, leading to increased laxity of the rat patellar tendon and knee-related ligaments as well as an expanded range of passive knee motion. Multiple studies on Achilles tendon healing in mice have found that ERβ deficiency exerts adverse effects on tendon injury repair by impairing adipogenesis and type I collagen formation, resulting in reduced tendon stress, tensile strength, and cross-sectional area—specifically manifested as decreased cell proliferation and increased apoptosis [109–111]. These findings were further supported by a study in rats induced with an estrogen-deficient state similar to that of postmenopausal humans [112]. The molecular mechanisms underlying ERβ deficiency-induced reduction in tenocyte proliferation [109, 110], increased cell apoptosis, and impaired type I collagen formation are as follows: on one hand, ERβ deficiency upregulates the PPARγ signaling pathway, leading to increased adipocyte infiltration in tendon scars and abnormal healing; on the other hand, it downregulates the interferon regulatory factor 5-chemokine ligand 3 (IRF5-CCL3) axis during ECM remodeling, which inhibits type I collagen synthesis and interferes with Achilles tendon healing. Collectively, these studies indicate that ERβ expression enhances tendon cross-sectional area, stress resistance, and exercise capacity in experimental subjects, and it promotes tendon repair by regulating adipogenesis, type I collagen deposition, and reducing tenocyte apoptosis.

Furthermore, at the genetic level, Pontin et al. [113, 114] found in their study on posterior tibial tendon dysfunction in postmenopausal women that the XbaI single nucleotide polymorphism (SNP) in the ERα gene may contribute to tendinopathy, and the A/A genotype may be a risk factor for posterior tibial tendinopathy in this population. Consistent with this, another study on ER polymorphisms in patients with posterior tibial tendinopathy observed that patients carrying the XbaI SNP in the ER1 gene had a higher risk of developing posterior tibial tendinopathy [114, 115].

Epidemiological studies have shown that in young and healthy women, higher estrogen levels are associated with greater elasticity of the anterior cruciate ligament (ACL) and knee-related attached tendons compared to usual [116]. Meanwhile, in postmenopausal women with greater trochanteric pain, high estrogen levels are speculated to be associated with tendon stability [116]. Furthermore, in an experiment comparing patellar tendon stiffness between obese women and men, women were found to have lower patellar tendon stiffness than men [117]. Researchers hypothesized that this phenomenon may be due to the combination of elevated estrogen levels and obesity leading to reduced collagen synthesis and subsequent decreased tendon stiffness. In active young female athletes, high estrogen concentrations may significantly increase the risk of tendon and ligament injuries, as the combination of high estrogen levels and above-average physical activity appears to reduce the responsiveness of collagen synthesis to mechanical loading and is associated with increased joint laxity [118–120]. In current research, high estrogen levels have consistently been found to exert adverse effects on tendon homeostasis; such impacts manifest in aspects including tendon elasticity, stiffness, and laxity, and interact with factors such as obesity and physical activity to modulate tendon homeostasis.

One hypothesis regarding the molecular mechanism is that estrogen exerts indirect effects by influencing other hormonal components of the human endocrine system [121, 122]. High circulating levels of estradiol in women have been shown to be associated with low levels of free circulating insulin-like growth factor (IGF), which is a substance potentially directly linked to the magnitude of exercise-induced collagen synthesis. In studies investigating the effect of estradiol on tendons following exercise, a selective increase in tendon collagen synthesis was observed within 24 h after exercise, which is consistent with the experimental hypothesis that estradiol inhibits exercise-induced collagen synthesis in human tendons [123]. Researchers speculate that the underlying molecular mechanism may involve the indirect effect of high estradiol levels reducing the concentration of free circulating insulin-like growth factor.

In addition to investigating the impact of high estrogen concentrations on tendinopathy, estrogen deficiency in ovariectomized rats has been confirmed to impair the biomechanical properties of bone-tendon healing and inhibit the formation of cartilage tissue in the repair tissue [124]. An in vitro study on isolated Achilles tendons from ovariectomized, young, and aged rats verified that both aging and estrogen deficiency exert adverse effects on tendon metabolism and healing [86–88, 94, 112, 124–127]. Furthermore, Hsieh et al. [128], in their study on the relationship between ERβ and tendinopathy progression in rats, observed higher ERβ expression and a greater number of apoptotic cells in lesioned rats, which were correlated with the severity of the disease. The underlying mechanism is that under estrogen deficiency, upregulation of ERβ levels and induction of cell apoptosis promote disease progression and exacerbate pathological conditions. Similarly, a study by Irie et al. [129] found that postmenopausal estrogen deficiency may downregulate tendon collagen turnover, reducing tendon elasticity, stress, stiffness, and tensile strength. Thus, estrogen deficiency exerts negative effects on tendon metabolism and healing [130].

In summary, estrogens contribute to tendon anabolism and acute injury repair; however, both estrogen deficiency and excessive levels may disrupt tendon matrix homeostasis, thereby increasing tendon susceptibility to chronic degenerative changes when exposed to prolonged mechanical overuse or metabolic disturbances (e.g., obesity, hyperglycemia). Notably, the precise role of estrogen in tendon physiology remains incompletely elucidated [91]; it appears to depend on factors such as the age and hormonal status of females, the specific type of tendons and ligaments involved in the lesion, and the degree of mechanical loading on the tissue. Supporting these observations, Animal studies have demonstrated that estrogen deficiency may reduce tendon collagen synthesis efficiency, decrease tendon elasticity, and inhibit tendon anabolism, thereby being detrimental to tendon injury repair. In contrast, normal levels of estrogen may stimulate the synthesis of type I collagen in tendons and promote tenocyte proliferation and metabolism. These findings provide a basis for exploring estrogen as a therapeutic strategy to modulate tendon matrix homeostasis and reduce susceptibility to degenerative changes.

The cellular senescence-senescence-associated secretory phenotype (SASP) pathogenic axis

Aging serves as a pivotal predisposing factor for tendinopathy, with tendon aging correlating to a rising incidence of tendon injuries and/or chronic tendon disorders like tendinopathy itself. Over the course of an individual’s lifespan, the occurrence of microtrauma and subclinical inflammation in aged or overused tendons progressively gives rise to pain, swelling, and physical impairment [131]. Aged tendons are typically characterized by a diminished quantity and compromised functionality of TSPCs, fragmented or disorganized collagen bundles, and augmented deposition of glycosaminoglycans (GAGs)—all of which culminate in pain, inflammation, and impaired mobility. Notably, aging exerts profound impacts on tendons across molecular, cellular, and whole-organ dimensions. From a biological perspective, reduced cellularity, impaired cellular function, and a degenerated, inflamed microenvironment stand as hallmark features of aging tendons [132]. In terms of biomechanics, aged tendons exhibit decreased stiffness and tensile strength, rendering them more vulnerable to injuries [133].

Tendon cells derived from aged individuals exhibit compromised motility and proliferative capacity, impaired protein biosynthetic activity, as well as diminished responsiveness to mechanical stimuli [132, 134]. Cellular capacity for migration toward injury sites, coupled with robust metabolic activity, serves as a prerequisite for their involvement in wound healing. In elderly individuals, tendon cells demonstrate diminished motility—including impaired adhesion and migration—which is hypothesized to contribute to the compromised tendon healing potential [135, 136]. Mechanistically, the reduced motility of tendon cells is closely linked to alterations in actin fiber arrangement and focal adhesions (FAs). Key components of FAs, such as focal adhesion kinase (FAK), paxillin, and talin, play pivotal roles in regulating cellular behavior [136–138]. Arnesen and colleagues documented that these FA-related proteins are predominantly localized on the cell surface of young tendon fibroblasts, whereas they cluster around the nucleus in aged tendon fibroblasts [136]. Given that FAs are critical for generating the traction force required for cell migration, the lack of FAs on the cell surface may impair the adhesion and migration efficiency of tendon cells in aged mammals [136].

Notably, the global metabolic activity of tendon cells also declines with advancing age. A seminal study revealed that tissue slices from rabbit Achilles tendons rely on elevated aerobic glycolysis as the primary energy supply during the first three months of extrauterine life, which subsequently undergoes a gradual decline. In contrast, anaerobic glycolysis maintains relative stability across the entire lifespan [139]. These reductions in migratory capacity and perturbations in metabolic activity collectively offer a plausible explanation for the impaired tendon healing observed in elderly individuals.

Typically, the capacity for protein biosynthesis in aged tenocytes is diminished, a phenomenon likely linked to alterations in intracellular organelles—such as the rough endoplasmic reticulum and mitochondria [140]—as well as disrupted intercellular crosstalk [141]. Sugiyama and colleagues documented that in the flexor tendons of mice, the mRNA expression levels of collagens (type I and type III) and tendon-specific markers (Mohawk homeobox (MKX), scleraxis (SCX), and tenomodulin (TNMD)) undergo a substantial decline with advancing age [142]. Consistent with these findings, transmission electron microscopic observations revealed that compared to adult rat fibrocartilage cells at the bone-tendon junction, aged cells exhibit shorter and sparser cytoplasmic processes. This structural change translates to a contracted Golgi network and compromised protein synthesis capacity, accompanied by a reduction in the number of rough endoplasmic reticulum cisterns and mitochondria [140].

With the progression of aging, TSPCs gradually lose their self-renewal capacity and the ability to maintain their population size, ultimately leading to depletion. This process can be further expedited—for instance, via premature senescence triggered by the activation of cellular defense mechanisms [143]. Kohler and colleagues reported that aged TSPCs undergo premature cellular senescence, a phenomenon that reflects a notable transcriptomic shift. Among the most differentially expressed genes in this shift are those associated with the regulation of cell adhesion, migration, actin cytoskeleton, and dysregulated cell-matrix crosstalk [143]. Consequently, the aforementioned age-related alterations in TSPCs may disrupt tissue homeostasis.

At the mechanistic level, signaling molecules such as Rho-associated protein kinase (ROCK) have been extensively investigated in the context of TSPC aging and degeneration. ROCK serves a pivotal function in various aging-related cellular processes, including cell morphology, mitosis, motility, and senescence [144]. In aged tendon fibroblasts, the expression level of GADD153 is significantly higher than that in young tendon fibroblasts, indicating a greater accumulation of unfolded or misfolded proteins in aged tendon fibroblasts [136]. Additionally, several other potential mechanisms have been recently identified to be involved in TSPC senescence and repair capacity [145–150]. These mechanisms involve molecules such as Cbp/p300-interacting transactivator 2 (CITED2, a transactivator responsive to multiple stimuli), CD44 (a matrix assembly and organization protein implicated in tendon healing), TNMD (a well-recognized gene marker for the tendon and ligament lineage that regulates cell proliferation and adhesion), peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1, a highly conserved peptidylprolyl isomerase (PPI) with anti-aging effects in TSPCs), aquaporin 1 (AQP1, a member of the small water-transporting membrane protein family), forkhead box (FOX) P1 (FOXP1, a member of the P subfamily of the FOX transcription factor family), and connective tissue growth factor (CTGF, a cysteine-rich secretory protein belonging to the cellular communication network family).

With the progression of aging, collagen biosynthetic capacity undergoes a gradual diminishment through a multitude of mechanisms, encompassing the exhaustion of tenocytes specialized in collagen secretion and their progenitor TSPCs, enhanced degradation mediated by remodeling enzymes, as well as post-transcriptional modifications including hydroxylation, glycosylation, and AGE-mediated crosslinking [151, 152]. Consequently, the ECM of aged tendons is frequently characterized by decreased collagen fibril diameter, along with fragmented and disorganized collagen fibers [151, 153]. Aging-related alterations in the structure of collagen are anticipated to exert a substantial influence on the biomechanical characteristics of tendons [154]. Specifically, phenomena documented during the aging process—including diminished tensile strength, modified viscoelasticity, restricted fiber sliding, and enhanced stiffness—are closely linked to these structural changes [132].

Furthermore, accumulation of AGEs in aged tendons impairs ATP generation and cellular proliferative capacity, and is closely associated with ECM degradation and cellular apoptosis—collectively compromising normal cellular function and tissue regeneration [135, 155, 156]. Notably, the degenerative changes in the vascular network of aged tendons interfere with the recruitment of immune cells from the bloodstream [157, 158], ultimately leading to reduced nutritional supply, suppressed cell proliferation, and impaired ECM synthesis.

Aged tendons also exhibit greater vulnerability to injuries—including microtears—and possess an impaired capacity to regulate inflammation, a combination that gives rise to a state of chronic low-grade inflammation referred to as “inflammaging” [132, 135, 159]. At the mechanistic level, tendon inflammaging involves increased immune cell infiltration, upregulated cytokine expression, and enhanced ECM degradation [3, 132]. Moreover, numerous studies indicate that elderly individuals have diminished antioxidant defense mechanisms against hypoxia, coupled with elevated levels of circulating mitochondrial DNA (mtDNA) and prostaglandin E2 (PGE2)—factors that play a pivotal role in sustaining chronic low-grade inflammation [22, 132, 160]. Collectively, inadequate cellularity and compromised cell function, an imbalance between ECM synthesis and degradation, reduced tendon biomechanical strength and viscoelasticity, as well as a diminished capacity to resolve inflammation, can synergistically precipitate the occurrence of microdamage or sudden tendon ruptures, while also impairing tissue healing potential [3].

The release of SASP stands as a defining feature of both cellular senescence and organismal aging [161], encompassing proteins, lipids, extracellular vesicles, and non-coding nucleic acids that are involved in regulating diverse aging-related biological processes [162]. Notably, SASP plays a pivotal function in immune modulation and tissue aging: prior research has demonstrated that it fosters inflammation while contributing to immunosuppression [162]. Elevated SASP expression within the injured microenvironment of aged tendons correlates with an increase in the number of senescent cells. The accumulation of senescent TSPCs and the release of SASP induce chronic inflammation in tendon tissues [163], which further accelerates tissue-specific adult stem cell senescence and the accumulation of inflammatory factors through reactive oxygen species (ROS)-driven mitochondrial damage, perpetuating a vicious cycle that leads to cellular dysfunction and impairs tendon tissue remodeling and regeneration [164–168].

The establishment of a novel clinical management paradigm for tendinopathy

Given the role of the metabolic-endocrine-aging axis as a critical susceptibility modifier (Table 1), clinical management of tendinopathy should shift from traditional local repair to a systemic-local integrated paradigm. As tendon degeneration reflects a local manifestation of systemic dysfunction, conventional local interventions cannot fully reverse the progressive damage driven by metabolic, hormonal, and aging-related alterations.

Table 1.

In Vitro/In Vivo Studies Supporting Tendinopathy’s Four Systemic Pathogenic Axes

Pathogenic Axis	Study Design	Study population/Model	Key outcomes
Hyperglycemia-AGE	In vitro (cell culture)	Rat Achilles tendon cells; tendon cells	High glucose upregulated MMP-9/MMP-13 and MMP-2/IL-6/TIMP-1/2/NOX4/type III collagen; increased ROS production, reduced type I collagen, impaired cell proliferation
Hyperglycemia-AGE	In vitro (cell culture)	Patellar tendon-derived stem cells (TDSCs); TDSCs from healthy/tendinopathic human tissues	High glucose induced TDSC apoptosis, impaired proliferation, reduced type I collagen/tendon marker expression; elevated COX-2 and downregulated ALOX15/FPR1/CMKLR2 in tendinopathic TDSCs, amplifying inflammation
Hyperglycemia-AGE	In vitro (cell culture)	Tenocytes; patellar TDSCs	AGEs induce collagen cross-linking, reducing fiber sliding/viscoelasticity and increasing tendon brittleness/stiffness; AGEs upregulate TG2, altering TDSC tenogenic differentiation
Dyslipidemia-Mediated Tendon Homeostasis Imbalance	In vivo (animal model + surgical repair model)	ApoE-deficient mice; HFD/LFD-fed mice (tail tendon + post-surgical tendon repair)	ApoE-deficient mice had higher cholesterolaemia; HFD-fed mice showed increased body mass/cholesterol and reduced tendon total modulus. Post-surgically, HFD group had increased stiffness, reduced MTP joint flexion, elevated gliding resistance, compromised mechanical performance, and long-term functional deficits.
Dyslipidemia-Mediated Tendon Homeostasis Imbalance	In vivo (animal model + surgical repair model)	HFD/LFD-fed mice; obese HFD-fed rats	Post-surgically: HFD group had smaller repair tissue area, reduced cellularity, poor collagen alignment, and persistent tendon adhesions; non-surgically: HFD group showed smaller fibril diameter, elevated GAG/hydroxyproline levels, increased fat infiltration and cell density
Sex Hormone Fluctuation-Mediated Endocrine Dysregulation	In vitro + clinical interventional/ observational study	Mouse masticatory muscle tendon cells; oral contraceptive (ethinylestradiol) users vs. controls	E2 promotes tenocyte proliferation/differentiation and tendon hyperplasia; estrogen + exercise enhances collagen synthesis efficiency; oral contraceptive users have slower tendon collagen turnover
Sex Hormone Fluctuation-Mediated Endocrine Dysregulation	Clinical observational + in vivo (animal model)	Postmenopausal women (carpal tunnel syndrome, torn supraspinatus); male/female posterior tibial tendon dysfunction; ERβ-deficient mice; estrogen-deficient rats	ERβ overexpression promotes inflammation/angiogenesis and increases ligament laxity; ERβ deficiency impairs Achilles tendon healing (abnormal adipogenesis, reduced type I collagen, decreased tenocyte proliferation, increased apoptosis); ERα plays no dominant role
Sex Hormone Fluctuation-Mediated Endocrine Dysregulation	In vitro + in vivo (animal model)	Ovariectomized rats; isolated Achilles tendons from young/aged/ ovariectomized rats	Estrogen deficiency impairs bone-tendon healing biomechanics, inhibits cartilage formation, and synergizes with aging to disrupt tendon metabolism; postmenopausal estrogen deficiency downregulates collagen turnover, reducing tendon elasticity/stiffness/tensile strength
Cellular Senescence-SASP Cascade	In vitro + observational study	Aged human/mammalian tendon cells/fibroblasts; young tendon fibroblasts (control)	Aged tendon cells show impaired motility, proliferation, protein synthesis and mechanical stimulus responsiveness; FA-related proteins (FAK/paxillin/talin) cluster around nucleus (vs. cell surface in young cells), with actin fiber arrangement alteration, leading to reduced adhesion/migration and compromised tendon healing potential
Cellular Senescence-SASP Cascade	In vitro + in vivo (animal model)	Aged tendons; senescent TSPCs	Aged tendon injury microenvironment: elevated SASP correlates with more senescent cells; senescent TSPCs and SASP induce tendon chronic inflammation, accelerate stem cell senescence and inflammatory factor accumulation via ROS-mediated mitochondrial damage, form a vicious cycle, and impair tendon remodeling and regeneration

Clinical practice should attach great importance to the assessment and targeted modulation of systemic risk factors. Alleviating systemic dysregulation may help restore the tendon’s physiological microenvironment, enhance intrinsic repair capacity, and promote long-term structural and functional stability—transcending temporary symptomatic relief. Given interindividual heterogeneity in systemic profiles, personalized therapeutic regimens tailored to individual pathogenic contexts lay a solid foundation for improved efficacy and sustainable outcomes.

For patients with tendinopathy secondary to diabetes mellitus, treatment is likely to benefit from interventions including daily exercise to promote glycaemic control (reducing the deleterious effects of advanced glycation end-products (AGEs) on tendon health), aerobic training, and resistance training—with slower, more careful load progression than in non-diabetic patients—given that diabetes impairs tendon function [169].

For obese patients, a rational dietary regimen should be prioritized. This includes but is not limited to: (1) limiting intake of high-fat products, processed foods and sugars; (2) increasing consumption of low-AGE, high-leucine and high-glycine foods (e.g., fish, legumes, low-fat dairy products and vegetables); and (3) adopting appropriate food processing practices—specifically avoiding high-temperature, low-moisture cooking methods, which correlate with elevated AGE synthesis [170]. Olive oil enriched with the AGE inhibitor aminoguanidine or the antioxidant BHT can completely or partially inhibit heat-induced AGE formation. Marinating meat in acidic solutions (e.g., lemon juice, vinegar) can also reduce AGE generation during cooking [171]. Thus, dietary regulation can alleviate tendon degeneration by exerting tendon-protective effects, such as enhanced ECM synthesis and improved tendon biomechanical properties.

For patients with estrogen deficiency, particularly those in a hypogonadal postmenopausal state, estrogen replacement therapy (ERT) is a beneficial option for tendons [130], as it helps normalize tendon function. Preliminary studies have shown that ERT confers benefits at least in active postmenopausal women and may reduce the risk of lower extremity tendon and ligament injuries [118]. Furthermore, the effects of estrogen levels on tendinopathy are gradual and progressive. Studies examining the in vivo mechanical properties of the medial gastrocnemius tendon throughout the menstrual cycle [172–175] have revealed that acute estrogen fluctuations exert no significant impact on the tendon’s mechanical properties. Additionally, ERT administered after tendon injury does not induce rapid changes in the tendon’s mechanical or histological parameters [174]. There also appears to be no obvious correlation between acute transient estrogen deficiency and tendon mechanical properties. Thus, long-term adherence to ERT is required to yield positive effects in tendinopathy management.

For elderly patients, exercise boosts tendon healing and reverses age-related harm in animal models and humans [176–182]. It also upregulates cell proliferation/differentiation, growth factor expression, ECM synthesis, and inhibits calcification [183]. Specifically, mechanical stimuli perturb cells via ECM-FA interactions, triggering cytoskeleton-mediated intracellular signaling and tenogenic marker SCX gene expression [184]. Accordingly, it elevates collagen fibril density, quantity, size and turnover, and fosters immature collagen accumulation with less glycation and crosslinking. Conversely, excessive stretching of senescent TSPCs elevates non-tenogenic gene expression [185].

Apart from tailored exercise for age-related tendon injuries, studies show that adding partial vascular occlusion (BFR) to low-load resistance training (20–40% 1 repetition maximum [1RM]) induces favorable muscular adaptations (e.g., muscle hypertrophy and strength gains similar to conventional high-load [HL] training) [186–188]. A systematic review and meta-analysis specifically focusing on older adults further confirmed that BFR combined with resistance training not only enhances muscle strength but also modulates biomarkers associated with musculoskeletal function [189], providing robust evidence for its applicability in elderly populations. Centner et al. recently showed that low-load BFR also improves Achilles tendon mechanical and morphological properties as effectively as conventional HL training. This benefits those unable to tolerate heavy loads but desiring better myotendinous function [186]. Thus, exercise mitigates tendon aging/degeneration harm but must be tailored to individual physical capacities and needs.

Emerging regenerative therapeutic strategies have long been explored as promising complements to exercise-based interventions for optimizing tendon injury repair and reversing age-related tendon degeneration, with foundational investigations identifying growth factor therapy, gene therapy, and tissue engineering as core research directions for enhancing tendon healing outcomes and restoring native tissue biomechanical properties [190]. Beyond exercise interventions, the degenerative effects of aging on tendon-resident cells can be mitigated through cell rejuvenation strategies, which include the use of stimulatory or inhibitory agents to modulate crucial signaling pathways, reduce oxidative stress, and implement biomechanical conditioning. Specifically, targeting intrinsic mechanisms—such as membrane and mitochondrial proteins/transcription factors [148], Eph receptors, and Rho-kinase—and modulating the extrinsic microenvironment via young ECM coculture [191], three-dimensional (3D) biomaterial scaffold culture [192], and biomechanical stimulation have demonstrated promising efficacy in attenuating cellular senescence. Biomechanical stimulation serves as an additional approach to modulate the microenvironment and rejuvenate aged TSPCs. Accumulating evidence indicates that the biomechanical characteristics of the cell-seeding microenvironment play an indispensable role in regulating tenogenesis. For instance, an in vitro study demonstrated that moderate mechanical stretching (4.00%) enhances the proliferation, stemness, and tenogenic-related gene expression of TSPCs isolated from aged mice. In vivo experiments have further confirmed that moderate treadmill running in 9-month-old mice alleviates degenerative tendon phenotypes, including lipid deposition, proteoglycan (PG) accumulation, and tendon calcification [185].

The systemic-local integrated paradigm for tendinopathy management does not negate the necessity of local interventions; instead, it emphasizes a synergistic strategy where local treatments address acute symptoms and systemic modulation targets critical susceptibility modifiers (i.e., systemic factors). Specifically, the systemic-local integration may ideally follow three main principles that should guide clinical practice: (1) Acute symptom relief first: Local interventions are prioritized to alleviate pain and restore basic function, creating a favorable environment for systemic interventions to take effect; (2) Pathogenic susceptibility modulation: Concurrent with local treatment, systemic risk factors (as key susceptibility modifiers) are targeted based on patient-specific profiles; (3) Dynamic adjustment: The intensity and priority of systemic vs. local interventions are adjusted according to disease progression (e.g., reducing local analgesics as systemic regulation improves tendon homeostasis, or reinforcing local load management if mechanical overuse persists).

Conclusions

In conclusion, tendinopathy is not solely a local issue; the direct impact of systemic factors via the metabolic-endocrine-aging axis is undeniable. It is often a regional manifestation of systemic dysregulation. Factors including hyperglycemia-induced AGEs deposition, dyslipidemia-triggered metabolic inflammation, sex hormone fluctuations, and the cellular senescence-SASP cascade collectively disrupt tendon cell homeostasis, remodel extracellular matrix biomechanics, and impair repair capacity, lowering the tendon’s mechanical load threshold.

Since traditional local treatments rarely target these systemic roots, an urgent need exists to develop a novel tendinopathy clinical staging system incorporating systemic risk factors (e.g., metabolic status, hormonal profiles, aging-related biomarkers). To address this need, we propose the Systemic-Local Integrated Staging System for Tendinopathy—a concise classification framework defined as: a clinical staging tool that integrates two core dimensions (local tendon pathology severity and systemic risk factor load) to guide personalized intervention prioritization. Specifically, it quantifies local manifestations (e.g., pain intensity, functional impairment, tendon structural damage) and assesses systemic risk factor burden (e.g., metabolic control status, hormonal profile, aging-related biomarkers such as SASP factors or AGEs), aiming to balance local symptom relief and systemic risk modulation rather than relying solely on isolated local lesion characteristics. This system enables precise patient stratification, and an interdisciplinary approach integrating systemic risk management with targeted local interventions is key to halting tendinopathy progression and optimizing outcomes.

Current limitations and knowledge gaps

Despite the well-established roles of systemic metabolic–endocrine–aging status as a critical susceptibility modifier for tendinopathy, several important limitations and knowledge gaps remain in the current field. First, most mechanistic evidence is derived from preclinical in vitro and animal models, whereas high-quality longitudinal clinical studies remain limited, making it difficult to establish definitive causal relationships in human populations. Second, the crosstalk between different systemic factors (e.g., metabolic disorders, hormonal changes, and aging) remains poorly understood, and many integrated regulatory networks are still hypothetical rather than fully validated. Third, clinical translation of targeted interventions based on systemic modulation is still in its infancy, with few well-designed clinical trials evaluating efficacy and safety. Finally, individual variabilities such as age, sex, and comorbidities are rarely considered in current research designs, further limiting the clinical applicability of existing findings. Addressing these gaps will facilitate the development of more targeted systemic-local integrated therapeutic strategies for tendinopathy and improve clinical translation of basic research findings.

Author contributions

Yuqi Lin, Zhichao Liu and Lianjie Peng jointly participated in manuscript drafting, systematic literature search and data collation. Shihan Wang, Kun Li and Xingyu Lv designed and prepared the graphical content. Jianxiang He conceived the overall theme and provided critical guidance of the study.

Funding

The study did not receive any specific source of funding.

Data availability

Data sharing is not applicable to this article as no datasets were generated during thecurrent study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.