Tendinopathy is a condition characterized by persistent tendon pain, structural damage, and compromised functionality. Presently, the treatment for tendinopathy remains a formidable challenge, partly because of its unclear pathogenesis. Tendon stem/progenitor cells (TSPCs) are essential for tendon homeostasis, regeneration, remodeling, and repair. An innovative theory has been previously proposed, with insufficient evidence, that the erroneous differentiation of TSPCs may constitute one of the fundamental mechanisms underpinning tendinopathy. Over the past few years, there has been accumulating evidence for plausibility of this theory. In this review, we delve into alterations in the differentiation potential of TSPCs and the underlying mechanisms in the context of injury-induced tendinopathy, diabetic tendinopathy, and age-related tendinopathy to provide updated evidence on the erroneous differentiation theory. Despite certain limitations inherent in the existing body of evidence, the erroneous differentiation theory emerges as a promising and highly pertinent avenue for understanding tendinopathy. In the future, advanced methodologies will be harnessed to further deepen comprehension of this theory, paving the way for prospective developments in clinical therapies targeting TSPCs for the management of tendinopathy.

To identify risk factors for tendon healing failure following arthroscopic rotator cuff repair (ARCR) in patients with small to medium-sized rotator cuff tears (RCTs).

A retrospective study was conducted on 320 patients with RCTs who underwent arthroscopic repair between June 2018 and June 2021. All patients had at least 2 years of postoperative follow-up, with MRI scans at the final assessment. Based on MRI results, patients were categorized into the healing success group (Group A: types I-III) or the healing failure group (Group B: types IV-V). Variables associated with rotator cuff healing, including patient characteristics, baseline symptoms, imaging data, and surgery-related factors, were analyzed using univariate and multivariate logistic regression.

Healing failure occurred in 54 of the 320 patients (16.9%). Functional status improved significantly across all patients (P < 0.05), irrespective of healing outcomes. Multifactorial analysis identified smoking (OR = 1.931, P = 0.028), diabetes (OR = 3.517, P = 0.038), lower bone mineral density (BMD) (OR = 1.551, P = 0.018), higher fatty infiltration (FI) (OR = 4.025, P = 0.009), and smaller acromiohumeral distance (AHD) (OR = 2.546, P = 0.006) as independent risk factors for healing failure.

Smoking, diabetes, lower BMD, higher FI, and smaller AHD are independent risk factors for healing failure following ARCR.

Diabetes is one of the most common metabolic diseases worldwide, leading to complications, mortality, and significant healthcare expenditures, which impose a substantial social and financial burden globally. A diabetic environment can induce metabolic changes, negatively affecting tendon homeostasis, leading to alterations in biomechanical properties and histopathology. Numerous studies have investigated the mechanisms through which diabetes exerts pathological effects on tendons, including increased free radical production, oxidative stress, inflammatory responses, deposition of advanced glycation end products (AGEs), and microvascular changes. These metabolic changes damages tendon structure, biomechanics, and tendon repair processes. The proliferation of tendon stem cells decreases, apoptosis increases, and abnormal differentiation, along with abnormal expression of myofibroblasts, ultimately lead to insufficient tendon repair, fibrosis, and remodeling. Although researches unveiling the effects of diabetes on tendinopathy, fibrosis or contracture, and tendon injury healing are growing, systematic understanding is still lacking. Therefore, this review summarizes the current research status and provides a comprehensive overview, offering theoretical guidance for future in-depth exploration of the impact of diabetes on tendons and the development of treatments for diabetes-related tendon diseases.

Diabetic calcific tendinopathy is the leading cause of chronic pain, mobility restriction, and tendon rupture in patients with diabetes. Tendon stem/progenitor cells (TSPCs) have been implicated in the development of diabetic calcified tendinopathy, but the molecular mechanisms remain unclear. This study found that diabetic tendons have a hyperoxic environment, characterized by increased oxygen delivery channels and carriers. In hyperoxic environment, TSPCs showed enhanced osteogenic differentiation and increased levels of reactive oxygen species (ROS). Additionally, hypoxia-inducible factor-1a (HIF-1a), a protein involved in regulating cellular responses to hyperoxia, was decreased in TSPCs by the ubiquitin-proteasome system. By intervening with antioxidant N-acetyl-L-cysteine (NAC) and overexpressing HIF-1a, we discovered that blocking the ROS/HIF-1a signalling axis significantly inhibited the osteogenic differentiation ability of TSPCs. Animal experiments further confirmed that hyperoxic environment could cause calcification in the Achilles tendon tissue of rats, while NAC intervention prevented calcification. These findings demonstrate that hyperoxia in diabetic tendons promotes osteogenic differentiation of TSPCs through the ROS/HIF-1a signalling axis. This study provides a new theoretical basis and research target for preventing and treating diabetic calcified tendinopathy.

This review article presents the possibilities and limitations of histopathological diagnostics on the issues of joint diseases, including in the context of the medical insurance inquiries, which consider the important articular, non-osseous compartments, especially of the tendons, ligaments, and meniscus. Essential for expert assessments is the causal clarification of whether the continuity disruption has been induced exogenously by trauma or endogenously based on tissue that is functionally impaired and thus degeneratively altered. The degree of degeneration/texture disorder is determined by means of the degeneration-score, which is set in a semiquantitative, three-stage grading. Grades 1 and 2 are summed up as low-grade degeneration and compared to grade 3, high-grade degeneration. Age determination of continuity disruption is based on the assessment of the morphology of discontinuity and on the assessment of hemosiderin deposits. The tasks of histopathological diagnostics thus consist of the detection and grading of textural disorder (degeneration), the determination of the histopathologic age of existing continuity disruptions, and particularly the diagnosis of clinically/radiologically undiagnosed diseases, which may be relevant for pathogenesis. In the case of contradictory diagnoses from different diagnostic disciplines and in the case of imprecise and potentially even contradictory patient information, purely legal, judicial decisions may be necessary. In this case the legally binding assessment within the framework of legal evidence evaluation then arises.

The AGEs levels in tissues of diabetics and elderly tend to be higher than in normal individuals. This study aims to determine the effects of AGEs on Achilles tendon repair.

Thirty-six male eight-week-old Sprague Dawley rats were selected in this study. The rats were randomly divided into two experimental groups and a control group after the transection of the Achilles tendon. During the tendon repair, the experimental groups were injected around the Achilles tendon with 350mmol/L (low dose group) and 1000mmol/L (high dose group) D-ribose 0.2 ml respectively to increase the AGEs level, while in the control group were given the same amount of PBS. The injections were given twice a week for six weeks. Collagen-I, TNF-α, and IL-6 expression in the healed Achilles tendon was assessed. Additionally, macroscopic, pathological, and biomechanical evaluations of Achilles tendon repair were conducted.

The repaired Achilles tendons in the high dose group showed severe swelling and distinctive adhesions. The histological score went up with the increase of the AGEs in the Achilles tendon (p<0.001). TNF- α and IL-6 in the Achilles tendon increased (p<0.001, p<0.001), and the production of collagen-I decreased with the accumulation of AGEs in the repaired Achilles tendon (p<0.001). The tensile strength of Achilles tendon in the high dose group was impaired significantly.

In current study, the compromised tendon repair model induced by AGEs was successfully established in rat. The study demonstrated that AGEs significantly impair Achilles tendon repair.

Advanced glycation end products (AGEs) often accumulate in the Achilles tendon during the course of diabetes. This study aims to determine the impact of AGEs on tendon repair and explore the role of pioglitazone in mitigating this impact.

Forty-eight male 8 week-old Sprague Dawley rats were selected in this study. After transection of Achilles tendon, the rats were randomly divided into four groups. The Achilles tendons of rats were injected with 1000 mmol/L D-ribose to elevate the content of AGEs within the tendons in two groups, the remaining two groups received injections of phosphate buffered saline (PBS) solution. Subsequently, the first two groups were respectively received oral administration of pioglitazone (20 mg/kg/day) and PBS. The remaining two groups were given the same treatment. The expression of the collagen-I, TNF-α, IL-6 of the repaired tendon were detected. The macroscopic, pathologic and biomechanical aspects of tendon healing were also evaluated.

AGEs accumulation in tendon during the healing process increases the expression of inflammatory factors such as TNF-α and IL-6, leading to insufficient synthesis of collagen-I and delayed recovery of the tendon's tensile strength. Pioglitazone significantly attenuated the damage caused by AGEs to the tendon healing process, effectively improving the recovery of tendon tensile strength. Pioglitazone could not inhibit the generation of AGEs in the tissue and also had no impact on the normal healing process of the tendon.

Pioglitazone could prevent the deleterious impact of AGEs on the Achilles tendon healing and improve the biomechanical properties of the tendon.

Percutaneous Achilles tendon lengthening is an effective surgical procedure to treat and prevent forefoot and midfoot ulcerations in patients with diabetes. Patients with diabetes are prone to plantar ulcerations due to a combination of factors, such as peripheral neuropathy, decreased tendon elasticity, peripheral vascular disease, and hyperglycemia. Complications such as re-ulceration and transfer lesion to the heel, associated with a calcaneal gait secondary to over-lengthening, are possible with percutaneous Achilles tendon lengthening. Although percutaneous Achilles tendon lengthening is well accepted, the overall incidence of complication has not been well described. A systematic review of the reported data was performed to determine the incidence of complication for percutaneous tendo-Achilles lengthening when used for the treatment and prevention of diabetic plantar ulcerations. Nine studies involving 490 percutaneous lengthening procedures met the inclusion criteria. The overall complication rate was 27.8% (8% with transfer heel ulcerations). Given the high rate of complications associated with a percutaneous Achilles tendon lengthening, careful patient selection and consideration of these risks should be considered prior to proceeding with this procedure. Additional prospective comparative analyses with standardization of surgical technique, degrees of lengthening achieved, and post-operative weightbearing and immobilization modalities are needed to decrease incidence of complication and achieve higher healing rates.

The association of tendinopathy with diabetes has been well recognized. Tendon stem/progenitor cells (TSPCs) play critical roles in tendon repair, regeneration, and homeostasis maintenance. Diabetic TSPCs exhibit enhanced erroneous differentiation and are involved in the pathogenesis of diabetic tendinopathy, whereas the underlying mechanism of the erroneous differentiation of TSPCs remains unclear. Here, we showed that high glucose treatment promoted the erroneous differentiation of TSPCs with increased osteogenic differentiation capacity and decreased tenogenic differentiation ability, and stimulated the expression and further secretion of HMGB1 in TSPCs and. Functionally, exogenous HMGB1 significantly enhanced the erroneous differentiation of TSPCs, while HMGB1 knockdown mitigated high glucose-promoted erroneous differentiation of TSPCs. Mechanistically, the RAGE/β-catenin signaling was activated in TSPCs under high glucose, and HMGB1 knockdown inhibited the activity of RAGE/β-catenin signaling. Inhibition of RAGE/β-catenin signaling could ameliorate high glucose-induced erroneous differentiation of TSPCs. These results indicated that HMGB1 regulated high glucose-induced erroneous differentiation of TSPCs through the RAGE/β-catenin signaling pathway. Collectively, our findings suggest a novel essential mechanism of the erroneous differentiation of TSPCs, which might contribute to the pathogenesis of diabetic tendinopathy and provide a promising therapeutic target and approach for diabetic tendinopathy.

Diabetic tendinopathy is a common invalidating and challenging disease that may be treated using stem cells. However, the effects of adipose-derived mesenchymal stem cell conditioned medium (ASC-CM) in diabetic tendinopathy have never been explored.

The present study evaluated the effects of ASC-CM on morphology, cell viability, structure, and scratch wound closure of human tenocytes (HTNC) exposed to high glucose (HG).

Experimental study.

HTNC were exposed to HG (25 mM) for 7, 14 and 21 days with or without ASC-CM for the last 24 h. CM was collected from 4 × 105 ASCs, centrifuged for 10 min at 200 g and sterilized with 0.22 μm syringe filter.

At 7 days, HG-HTNC had decreased cell viability [72 ± 2%, p < 0.01 versus normal glucose (NG)] compared to NG-HTNC (90 ± 5%). A further decrement was detected after 14 and 21 days (60 ± 4% and 60 ± 5%, both, p < 0.01 versus NG and p < 0.01 versus HG7). While NG-HTNC evidenced a normal fibroblast cell-like elongated morphology, HG-HTNC showed increased cell roundness. In contrast, HG-HTNC exposed to ASC-CM showed a significant increase in cell viability, an improved cell morphology and higher scratch wound closure at all HG time points. Moreover, the exposure to ASC-CM significantly increased thrombospondin 1 and transforming growth factor beta 1 (TGF-β1) content in HG-HTNC. The TGF-β1 elevation was paralleled by higher Collagen I and Vascular Endothelial Growth Factor in HG-HTNC.

ASC-CM may restore the natural morphology, cell viability and structure of HTNC, promoting their scratch wound closure through TGF-β1 increase.

Tendinopathy describes a complex pathology of the tendon characterized by abnormalities in the microstructure, composition, and cellularity of the tendon, leading to pain, limitation of activity and reduced function. Nevertheless, the mechanism of tendinopathy has not been fully elucidated, and the treatment of tendinopathy remains a challenge. High mobility group box 1 (HMGB1), a highly conserved and multifaceted nuclear protein, exerts multiple roles and high functional variability and is involved in many biological and pathological processes. In recent years, several studies have suggested that HMGB1 is associated with tendinopathy and may play a key role in the pathogenesis of tendinopathy. Therefore, this review summarizes the expression and distribution of HMGB1 in tendinopathy, focuses on the roles of HMGB1 and HMGB1-based potential mechanisms involved in tendinopathy, and finally summarizes the findings on HMGB1-based therapeutic approaches in tendinopathy, probably providing new insight into the mechanism and further potential therapeutic targets of tendinopathy.

Metabolic diseases such as obesity and diabetes mellitus seem to have an influence on reoperation and long-term functional outcomes after arthroscopic repair of chronic rotator cuff tears. High prevalence of these pathologies can be found in the Canary Islands. A retrospective cohort study was carried out, in which 80 patients undergoing shoulder arthroscopic surgery for the repair of chronic rotator cuff tears were included, with a minimum follow up of 5 years, to study the occurrence of complications, reoperation, and functional outcomes. Functionality after surgery improved in 75% of patients with diabetes and remained the same or worsened in 25% (OR = 1.444). In the group of non-diabetic patients, 83.9% had improved function after surgery while it remained the same or worsened in 16.1% (OR = 0.830). Functionality after surgery improved in 76.6% of obese patients and remained the same or worsened in 23.4% (OR = 1.324). In the non-obese group, 87.9% had improved function after surgery, while it remained the same or worsened in 12.1% (OR = 0.598). Despite not obtaining statistically significant differences, the analysis of the results obtained suggests that obesity and diabetes could act by decreasing the subjective improvement in functionality after surgery, and, in the case of obesity, also increase the risk of reoperation.

Diabetes mellitus (DM) is associated with musculoskeletal complications-including tendon dysfunction and injury. Patients with DM show altered foot and ankle mechanics that have been attributed to tendon dysfunction as well as impaired recovery post-tendon injury. Despite the problem of DM-related tendon complications, treatment guidelines specific to this population of individuals are lacking. DM impairs tendon structure, function, and healing capacity in tendons throughout the body, but the Achilles tendon is of particular concern and most studied in the diabetic foot. At macroscopic levels, asymptomatic, diabetic Achilles tendons may show morphological abnormalities such as thickening, collagen disorganization, and/or calcific changes at the tendon enthesis. At smaller length scales, DM affects collagen sliding and discrete plasticity due to glycation of collagen. However, how these alterations translate to mechanical deficits observed at larger length scales is an area of continued investigation. In addition to dysfunction of the extracellular matrix, tendon cells such as tenocytes and tendon stem/progenitor cells show significant abnormalities in proliferation, apoptosis, and remodeling capacity in the presence of hyperglycemia and advanced glycation end-products, thus contributing to the disruption of tendon homeostasis and healing. Improving our understanding of the effects of DM on tendons-from molecular pathways to patients-will progress toward targeted therapies in this group at high risk of foot and ankle morbidity.

Pre-diabetes and diabetes are growing threats to the modern world. Diabetes mellitus (DM) is associated with comorbidities such as hypertension (83.40%), obesity (90.49%), and dyslipidemia (93.43%), creating a substantial burden on patients and society. Reductive and oxidative (Redox) stress level imbalance and inflammation play an important role in DM progression. Various therapeutics have been investigated to treat these neuronal complications. Melatonin and dipeptidyl peptidase IV inhibitors (DPP-4i) are known to possess powerful antioxidant and anti-inflammatory properties and have garnered significant attention in the recent years. In this present review article, we have reviewed the recently published reports on the therapeutic efficiency of melatonin and DPP-4i in the treatment of DM. We summarized the efficacy of melatonin and DPP-4i in DM and associated complications of diabetic neuropathy (DNP) and neuropathic pain. Furthermore, we discussed the mechanisms of action and their efficacy in the alleviation of oxidative stress in DM.

Tendinopathy is a challenging complication observed in patients with diabetes mellitus. Tendinopathy usually leads to chronic pain, limited joint motion, and even ruptured tendons. Imaging and histological analyses have revealed pathological changes in various tendons of patients with diabetes, including disorganized arrangement of collagen fibers, microtears, calcium nodules, and advanced glycation end product (AGE) deposition. Tendon-derived stem/ progenitor cells (TSPCs) were found to maintain hemostasis and to participate in the reversal of tendinopathy. We also discovered the aberrant osteochondrogenesis of TSPCs in vitro. However, the relationship between AGEs and TSPCs in diabetic tendinopathy and the underlying mechanism remain unclear. In this review, we summarize the current findings in this field and hypothesize that AGEs could alter the properties of tendons in patients with diabetes by regulating the proliferation and differentiation of TSPCs in vivo.