Understanding cellular and molecular mechanisms of pathogenesis of diabetic tendinopathy

Table 3 Cellular and molecular alterations in tenocytes and tendon stem/progenitor cells

Cell type	Cell source	Study type	Groups	Main results	Ref.
Tendon-derived fibroblasts	SD rat, Achilles tendon	In vitro	NG (5.5 mmol/L) and HG (25 mmol/L) with different concentrations of AGEs (0, 50, 100, and 200 μg/mL).	HG had no effect on cell proliferation and expressions of genes associated with extracellular matrix remodeling. AGEs impaired proliferative capacity, ATP production, and electron transport chain efficiency, coupled with alterations in mitochondrial DNA content and expression of genes associated with extracellular matrix remodeling, mitochondrial energy metabolism, and apoptosis. While HG condition did impact some mitochondrial parameters, AGEs appear to be the primary insult and may be responsible for the development of the diabetic tendon phenotype.	Patel et al[51], 2019
Tenocytes	SD rat, Achilles tendon	In vitro and in vivo	CG (12 mmol/L) and HG (33 mmol/L)	Significantly higher gene expressions of NOX1, NOX4, MMP-2, TIMP-1, TIMP-2, IL-6, Col III and ROS accumulation but lower cell proliferation and type I collagen expression in HG than those in CG.	Ueda et al[42], 2018
Tenocytes	SD rat, Achilles tendon	In vitro	LG (5.5 mmol/L) and HG (25 mmol/L)	High glucose-treated tenocytes expressed higher levels of the adipogenic transcription factors PPARγ and C/EBPs. Increased adipogenic trans-differentiation and decreased cell migration induced by high glucose.	Wu et al[41], 2017
Tenocytes	SD rat, Achilles tendon	In vitro	LG (5.5 mmol/L) and HG (25 mmol/L)	No significant effect on cell growth and apoptosis between LG and HG. Increased glucose uptake and consumption in HG condition. Significantly decreased expression of tendon-related genes, including Egr1, Mkx, TGF-β1, Col1a2, and Bgn, in HG culture.	Wu, et al[39], 2017
Tenocytes	Human, hamstring tendon	In vitro	LG (5 mmol/L) and HG (17.5 mmol/L)	Apoptosis level of tenocytes was 1.5 times greater in peroxide-treated cells cultured in HG compared with untreated controls, while apoptosis level of tenocytes was not increased in peroxide-treated cells cultured in low glucose. Peroxide-treated tenocytes cultured in low glucose expressed higher RNA levels of col1a1 and col1a2.	Poulsen, et al[57], 2014
Tenocytes	SD rat, Achilles tendon.	In vitro	LG (6 mmol/L) and HG (12 mmol/L and 25 mmol/L)	The glucose concentration did not affect tendon cell proliferation. The mRNA expression of MMP-9 and MMP-13 was up-regulated by treatment with 25 mmol/L glucose, whereas the mRNA expression of type I and III collagen was not affected. 25 mmol/L glucose increased the enzymatic activity of MMP-9.	Tsai et al[50], 2013
Tenocytes	Porcine, patellar tendon.	In vitro	LG (5.5 mmol/L) and HG (25 mmol/L)	Exposure to HG or AGEs did not affect cell viability. Significantly decreased PG levels in tendons exposed to HG. Relative mRNA levels of biglycan and veriscan were unchanged in HG. Levels of fibromodulin were modestly increased, whereas mRNA for decorin and lumican were significantly decreased. High glucose media decreased PG production by tenocytes whereas AGE-modified type I collagen and free radical scavengers had no effects. High glucose conditions increase TGFβ1 levels in tenocyte.	Burner et al[52], 2012
Tenocytes	Porcmine, patellar tendon	In vitro	NG (5.5 mmol/L) and HG (25 mmol/L)	Significantly higher Tgase activity in tenocytes incubated in HG. CML-Collagen stimulated Tgase activity in tenocytes in both normal and high glucose media but did not induce markers of apoptosis or alter cell viability. Antioxidants reduced the effect of CML-Collagen on tenocytes Tgase activity.	Rosenthal et al[58], 2009
TDSCs	Human, patellar tendon, rotator cuff and hamstring tendons.	In vitro	LG (5.5 mmol/L) and HG (11.1 mmol/L)	HG stimulated inflammation and weakened pro-resolving inflammation response in TDSCs.	Kwan et al[87], 2020
TDSCs	SD rats, Achilles tendon	In vitro and in vivo	CG and AGEs-treated group	AGEs decreased the cell viability, induced apoptosis and senescence of TDSCs, exacerbated osteogenic differentiation of TDSCs and led to more ectopic calcification in Achilles tendon.	Xu et al[83], 2020
TPCs	Horses, superficial digital flexor tendons	In vitro	CG and insulin-treated group (insulin concentrations: 0, 0.07, 0.7 nmol/L)	Insulin increased proliferation and osteogenic differentiation of TPCs in vitro, with the increased ALP activity and elevated expression of osteogenic genes including Runx2, ALP and osteonection.	Durgam et al[84] 2019
TDSCs	SD rats, patellar tendon	In vitro	Non-diabetic TDSCs and diabetic TDSCs	Significantly decreased colony-forming ability, cell proliferation and tenogenic differentiation ability and increased osteogenic and chondrogenic differentiation ability were demonstrated in diabetic TDSCs.	Shi et al[40], 2019
TDSCs	SD rats, patellar tendon	In vitro	LG (5.5 mmol/L) and HG (15 mmol/L, 25 mmol/L)	High glucose could inhibit proliferation, induce cell apoptosis and suppress the tendon-related markers expression of TDSCs.	Lin et al[82], 2017

SD: Sprague-Dawley; NG: Normal glucose; LG: Low glucose; HG: High glucose; AGEs: Advanced glycation end-products; CG: Control glucose; ROS: Reactive oxygen species; PPARγ: Peroxisome proliferator-activated receptor γ; Egr1: Early growth response factor 1; Mkx: Mohawk; TGF-β1: Transforming growth factor beta 1; Bgn: Biglycan; PG: Proteoglycans; Tgase: Transglutaminase; CML: Carboxymethyl-lysine; TDSCs: Tendon derived stem cells; ALP: Alkaline phosphatase; Runx2: Runt-related transcription factor 2; NOX: NADPH oxidase; TPCs: Tendon progenitor cells; MMP: Matrix metalloproteinase; IL-6: Interleukin-6; TIMP: Tissue inhibitor of metalloproteinases; Col III: Collagen III.