Hyperglycemia Augments the Adipogenic Transdifferentiation Potential of Tenocytes and Is Alleviated by Cyclic Mechanical Stretch

Abstract

Diabetes mellitus is associated with damage to tendons, which may result from cellular dysfunction in response to a hyperglycemic environment. Tenocytes express diminished levels of tendon-associated genes under hyperglycemic conditions. In contrast, mechanical stretch enhances tenogenic differentiation. However, whether hyperglycemia increases the non-tenogenic differentiation potential of tenocytes and whether this can be mitigated by mechanical stretch remains elusive. We explored the in vitro effects of high glucose and mechanical stretch on rat primary tenocytes. Specifically, non-tenogenic gene expression, adipogenic potential, cell migration rate, filamentous actin expression, and the activation of signaling pathways were analyzed in tenocytes treated with high glucose, followed by the presence or absence of mechanical stretch. We analyzed tenocyte phenotype in vivo by immunohistochemistry using an STZ (streptozotocin)-induced long-term diabetic mouse model. High glucose-treated tenocytes expressed higher levels of the adipogenic transcription factors PPARγ and C/EBPs. PPARγ was also highly expressed in diabetic tendons. In addition, increased adipogenic differentiation and decreased cell migration induced by high glucose implicated a fibroblast-to-adipocyte phenotypic change. By applying mechanical stretch to tenocytes in high-glucose conditions, adipogenic differentiation was repressed, while cell motility was enhanced, and fibroblastic morphology and gene expression profiles were strengthened. In part, these effects resulted from a stretch-induced activation of ERK (extracellular signal-regulated kinases) and a concomitant inactivation of Akt. Our results show that mechanical stretch alleviates the augmented adipogenic transdifferentiation potential of high glucose-treated tenocytes and helps maintain their fibroblastic characteristics. The alterations induced by high glucose highlight possible pathological mechanisms for diabetic tendinopathy. Furthermore, the beneficial effects of mechanical stretch on tenocytes suggest that an appropriate physical load possesses therapeutic potential for diabetic tendinopathy.

Different Frequency of Cyclic Tensile Strain Relates to Anabolic/Catabolic Conditions Consistent with Immunohistochemical Staining Intensity in Tenocytes

“…Enhanced gene expression of Col1, decorin, hyaluronic acid, and its receptor (CD44) but no increase in MMP-3 was seen in tenocytes subjected to 5% stretch [24][25][26]. In addition, a 0.5-1 Hz frequency has been adopted in most mechanical studies for tenocytes because these conditions are postulated to be physiological [24,[27][28][29][30]. Our mechanical protocol with 5% strain and 1 Hz frequency seemed to be suitable to represent tenocyte anabolism.…”

Tendon stem cell-derived exosomes regulate inflammation and promote the high-quality healing of injured tendon

“…Rat tenocyte isolation and culture were performed as previously described by Shi and Wu [17,18]. Briefly, the tendon tissue from rat was cut into small pieces and placed in six-well culture plates.…”

Understanding cellular and molecular mechanisms of pathogenesis of diabetic tendinopathy

“…Our previous work[ 40 ] demonstrated microtears, red blood cells, small blood vessels, and changes in the rounding of tendon cells surrounding the tear sites in diabetic tendons, and IHC staining of diabetic patellar tendons showed increased expression of osteochondrogenic differentiation markers, including osteopontin (OPN), osteocalcin (OCN), Sox9, and Col II, and reduced expression of tenogenic markers, including Col I and tenomodulin (Tnmd). In addition, Wu et al [ 41 ] reported increased peroxisome proliferator-activated receptor γ (PPARγ)-positive, rounded cells residing in diabetic tendons, which were aligned along the collagen fibrils. Phenotypic variations in tendon cells may accelerate the degeneration of diabetic tendons, deteriorating the biomechanical properties of the tendons.…”

“…The main findings are summarized in Table 3 . Some researchers have shown that the proliferation of tenocytes is significantly decreased[ 42 ] and that cell migration, a crucial tenocyte function, is retarded under high glucose conditions[ 41 ]. Therefore, hyperglycemia might inhibit the ability of cells to repair damaged or degenerated tendons.…”