Search

Ectopic tendon mineralization can develop following tendon rupture or trauma surgery. The pathogenesis of ectopic tendon mineralization and its clinical impact have not been fully elucidated yet. In this study, we utilized a mouse Achilles tendon injury model to determine whether ectopic tendon mineralization alters the biomechanical properties of the tendon and whether BMP signaling is involved in this condition. A complete transverse incision was made at the midpoint of the right Achilles tendon in 8-week-old CD1 mice and the gap was left open. Ectopic cartilaginous mass formation was found in the injured tendon by 4 weeks post-surgery and ectopic mineralization was detected at 8 to 10 weeks post-surgery. Ectopic mineralization grew over time and volume of the mineralized materials of 25-weeks samples was about 2.5 fold bigger than that of 10-weeks samples, indicating that injury-induced ectopic tendon mineralization is progressive. In vitro mechanical testing showed that max force, max stress and mid-substance modulus in the 25-weeks samples were significantly lower than the 10-weeks samples. We observed substantial increases in expression of bone morphogenetic protein family genes in injured tendons 1 week post-surgery. Immunohistochemical analysis showed that phosphorylation of both Smad1 and Smad3 was highly increased in injured tendons as early as 1 week post-injury and remained high in ectopic chondrogenic lesions 4-weeks post-injury. Treatment with the BMP receptor kinase inhibitor (LDN193189) significantly inhibited injury-induced tendon mineralization. These findings indicate that injury-induced ectopic tendon mineralization is progressive, involves BMP signaling and associated with deterioration of tendon biomechanical properties. [ABSTRACT FROM AUTHOR]

Tendon injuries are common, and the damaged tendon often turns into scar tissue and never completely regains the original biomechanical properties. Previous studies have reported that the mRNA levels of inflammatory cytokines such as IL-1β are remarkably up-regulated in injured tendons. To examine how IL-1β impacts tendon repair process, we isolated the injured tendon-derived progenitor cells (inTPCs) from mouse injured Achilles tendons and studied the effects of IL-1β on the inTPCs in vitro . IL-1β treatment strongly reduced expression of tendon cell markers such as scleraxis and tenomodulin , and also down-regulated gene expression of collagen 1 , collagen 3 , biglycan and fibromodulin in inTPCs. Interestingly, IL-1β stimulated lactate production with increases in hexokinase II and lactate dehydrogenase expression and a decrease in pyruvate dehydrogenase. Inhibition of lactate production restored IL-1β-induced down-regulation of collagen1 and scleraxis expression. Furthermore, IL-1β significantly inhibited adipogenic, chondrogenic and osteogenic differentiation of inTPCs. Interestingly, inhibition of tenogenic and adipogenic differentiation was not recovered after removal of IL-1β while chondrogenic and osteogenic differentiation abilities were not affected. These findings indicate that IL-1β strongly and irreversibly impairs tenogenic potential and alters glucose metabolism in tendon progenitors appearing in injured tendons. Inhibition of IL-1β may be beneficial for maintaining function of tendon progenitor cells during the tendon repair process. [ABSTRACT FROM AUTHOR]

Injured tendons do not regain their native structure except at fetal or very young ages. Healing tendons often show mucoid degeneration involving accumulation of sulfated glycosaminoglycans (GAGs), but its etiology and molecular base have not been studied substantially. We hypothesized that quality and quantity of gene expression involving the synthesis of proteoglycans having sulfated GAGs are altered in injured tendons and that a reduction in synthesis of sulfated GAGs improves structural and functional recovery of injured tendons. C57BL6/j mice were subjected to Achilles tendon tenotomy surgery. The injured tendons accumulated sulfate proteoglycans as early as 1‐week postsurgery and continued so by 4‐week postsurgery. Transcriptome analysis revealed upregulation of a wide range of proteoglycan genes that have sulfated GAGs in the injured tendons 1 and 3 weeks postsurgery. Genes critical for enzymatic reaction of initiation and elongation of chondroitin sulfate GAG chains were also upregulated. After the surgery, mice were treated with the 2‐deoxy‐d‐glucose (2DG) that inhibits conversion of glucose to glucose‐6‐phosphate, an initial step of glucose metabolism as an energy source and precursors of monosaccharides of GAGs. The 2DG treatment reduced accumulation of sulfated proteoglycans, improved collagen fiber alignment, and reduced the cross‐sectional area of the injured tendons. The modulus of the 2DG‐treated groups was higher than that in the vehicle group, but not of statistical significance. Our findings suggest that mucoid degeneration in injured tendons may result from the upregulated expression of genes involved the synthesis of sulfate proteoglycans and can be inhibited by reduction of glucose utilization. [ABSTRACT FROM AUTHOR]

Tendon repair follows a slow course of early inflammatory, proliferative and remodeling phases, which commonly results in the failure and loss of normal biomechanical properties. Previous studies have demonstrated that tendon-derived stem cells (TDSCs) are vital healing cells and that mRNA expression of anti-inflammatory cytokine interleukin (IL)-10 is significantly upregulated at the late inflammatory phase. To explore how IL-10 may impact tendon healing, the present study investigated the in vitro effects of IL-10 on TDSCs isolated from rat Achilles tendons. Cellular activities of TDSCs and the expression levels of tendon cell markers were measured treatment with IL-10 and subsequent performance of wound healing assays, reverse transcription-quantitative polymerase chain reaction and western blot analyses. The results demonstrated that IL-10 treatment markedly increased the proliferative capacity of TDSCs. In addition, IL-10 significantly enhanced cell migration when compared with the control cells. Furthermore, IL-10 treatment significantly activated the JAK/Stat3 signaling pathway and inhibited the protein expression of tendon cell markers, including scleraxis and tenomodulin. Notably, IL-10 treatment also reduced the gene expression levels of type 1 collagen, type 3 collagen, lumican and fibromodulin in TDSCs. These findings indicated that IL-10 enhanced cell proliferation and migration, and inhibited tenogenic differentiation in TDSCs in vitro. Reducing the negative effects whilst enhancing the positive effects of IL-10 may be a potential therapeutic target in tendon repair. [ABSTRACT FROM AUTHOR]