ArticleJournal of orthopaedic surgery and research2025
The HMGB1/RAGE/β-catenin axis mediates aberrant osteogenic-tenogenic differentiation imbalance of tendon stem/progenitor cells in diabetic tendinopathy.
Article in Journal of orthopaedic surgery and research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundTendinopathy is a common musculoskeletal disorder in individuals with diabetes. Tendon stem/progenitor cells (TSPCs) play an essential role in tendon repair, regeneration and homeostasis maintenance. Although studies have demonstrated that diabetic tendinopathy is closely associated with the altered differentiation of TSPCs, the underlying mechanisms remain largely unknown. This study was designed to investigate the role of the HMGB1/RAGE/β-catenin axis in the differentiation imbalance of TSPCs and diabetic tendinopathy.
methodsRat diabetes models were induced with streptozotocin (65 mg/kg). TSPCs were isolated at week 2 and the patellar tendons were isolated at weeks 2 and 4 for histological analysis. The activation of the HMGB1/RAGE/β-catenin axis in TSPCs and diabetic tendons was determined by western blot, ELISA, qRT-PCR and immunohistochemical staining. TSPCs and the diabetic tendons were then treated with lentivirus targeting HMGB1 or glycyrrhizin or FPS-ZM1 or PNU-74654 to demonstrate the role of this axis in TSPCs differentiation and diabetic tendinopathy. Alizarin red staining was performed to evaluate the calcium nodule formation. The mRNA expression of the osteogenic and tenogenic genes in TSPCs and diabetic tendons was examined by qRT-PCR and immunohistochemical staining. Recombinant HMGB1 was injected around the patellar tendons to further study the role of HMGB1 in tendinopathy, the histological changes were evaluated by HE stating and the expression of RAGE, β-catenin and the osteogenic genes in tendons was detected by immunohistochemical staining at weeks 2 and 4.
resultsWe established a rat diabetes model. In diabetic TSPCs, the activity of the HMGB1/RAGE/β-catenin axis was increased. Diabetic TSPCs exhibited increased osteogenic differentiation potential and reduced tenogenic differentiation ability. Blockade of this axis attenuated the differentiation imbalance of diabetic TSPCs. In addition, we also demonstrated the activation of the HMGB1/RAGE/β-catenin axis in diabetic tendons. The expression of tendon-related markers was decreased and the expression of osteogenic markers was increased in diabetic tendons. Inhibition of this axis could ameliorate these non-tenogenic alterations. Furthermore, injection of recombinant HMGB1 promoted the development of tendinopathy, increased the expression of RAGE and β-catenin and upregulated the expression of osteogenic markers in tendon tissue.
conclusionsOur findings revealed the critical role of the HMGB1/RAGE/β-catenin axis in the differentiation imbalance of TSPCs and diabetic tendinopathy, highlighting a novel essential mechanism involved in the pathogenesis of diabetic tendinopathy and providing a promising therapeutic target and approach for diabetic tendinopathy.
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