Understanding cellular and molecular mechanisms of pathogenesis of diabetic tendinopathy

Table 2 Histopathological features of diabetic tendinopathy

Species model	Tendon(s)	Groups	Duration of DM	Histopathological feature of diabetic tendons	Ref.
Human	Achilles tendons	CG and DG	Stage V diabetes patients	Diabetic tendons had mild impairment of collagen organization and focal collagen degeneration.	Guney et al[17], 2015
Human	Stenosing flexor tenosynovitis	CG and DG	DM for an average of 17 yr	SFTS in diabetic patients had fibrocartilage metaplasia including fibrocartilage-like cells, and granulation tissue contained newly formed microvessels stromal cells, a small number of inflammatory cells, and extracellular matrix that showed myxomatous degeneration.	Kameyama et al[18], 2013
Human	Rotator cuff tendon	CG and DG	DM for at least 5 yr	IHC showed increased MMP-9 and IL-6 in the torn tendon of diabetic patients.	Chung et al[46], 2017
Male C57Bl/6J mice	FDL tendons	CG (low fat diet) and DG (high fat diet)	At 40 wk post-induction	Lipid deposits were observed in the mid-substance of high fat diet-induced diabetic tendons.	Studentsova et al[30], 2018
C57BL/6 mice	Achilles tendons	CG and DG	DM for one-year post-induction	Fiber disorganization, uneven glycoprotein deposition, and increased interfibrillar spaces in diabetic tendon.	Wu et al[39], 2017
Male db/db C57BL/KsJ mice and wild type control C57BL/6 mice.	Achilles tendons	CG and DG	DM for 11 wk	Mild neutrophil infiltration, mild disorganization of the collagen fibers, mild increased basophilia of the tenocytes, and mildly increased nuclear size/rounding were observed in diabetic tendon. These pathologic changes are consistent with degenerative tendon.	Boivin et al[16], 2014
C57BL/6J Ob mice and wild-type mice	Achilles tendons	CG and DG (obese group, leptin-deficient)	12 wk	In diabetic Achilles tendon, some collagen fibers separated and lost their parallel orientation, with a decrease in fiber diameter and in density of collagen. Unequal and irregular crimping, loosening, increased waviness, lots of degeneration of tendon cells and chondrocyte-like cells were observed. Otherwise, diabetic tendons also showed obvious ruptures in insertion area, degeneration of tendinocytes, collagen fibers microtears, and vascular proliferation.	Ji et al[38], 2010
Male C57Bl/6J mice	FDL tendon	CG (low fat diet) and DG (high fat diet)	Surgery at 12 wk post-induction; days 7-28 post-repair.	After surgical transection injury, the diabetic tendons induced by high fat diet exhibited excess and prolonged scar tissue formation.	Ackerman et al[31], 2017
Male C57BL/6 mice	FDL tendons	CG (low fat diet) and DG (high fat diet)	Surgery at 12 wk post-induction; days 14 and 28 post-surgery.	Smaller cellular and fibrous repair tissue was observed at the injury site of diabetic tendons relative to non-diabetic tendons. The degree of collagen remodeling and fiber alignment in the injured area was less in the diabetic tendons.	David et al[32], 2014
SD rats	Patellar tendons	CG and DG	At 1, 2, and 4 wk post-induction.	Disordered arrangement of collagen fibers, micro-tears, red blood cells and small blood vessels, and the rounding changed tendon cells surrounding the tear sites were observed in the diabetic tendons. IHC staining of diabetic patellar tendons showed increased expression of osteo-chondrogenic differentiation markers including OPN, OCN, SOX9, and Col II, and reduced expression of tenogenic markers including Col I and TNMD.	Shi et al[40], 2019
SD rats	Achilles tendons	CG and DG	At 6 wk post-induction	No significant difference was observed in fibre structure, fibre arrangement, rounding of the nuclei, and regional variations in cellularity between diabetic and non-diabetic Achilles tendons. Immunohistochemical staining of the diabetic Achilles tendon showed markedly increased NOX1 expression within the tenocytes compared with the non-diabetic tendons.	Ueda et al[42], 2018
SD rats	Achilles tendons	CG and DG	DM for over 1 year post-induction	IHC: Increased PPARγ-positive, rounded cells were found to reside in the diabetic tendons, aligning along the collagen fibrils.	Wu et al[41], 2017
SD rats	Achilles tendons	CG, acute DG and chronic DG	1 wk for acute DM, 10 wk for chronic DM.	Total cell density and Achilles tendon cell proliferation were greater in the chronic diabetic tendons compared with the non-diabetic and acute diabetic tendons.	Volper et al[12], 2015
SD rats	Supraspinatus tendons	CG and hyperglycemia group	8 wk following hyperglycemia induction	Cell shape at the insertion site and mid-substance of the hyperglycemic tendon did not alter, nor did cell density at the insertion site; however, the hyperglycemic tendon had a greater cell density at the mid-substance of the tendon compared to the non-hyperglycemic group. Immunohistochemistry staining of the tendon demonstrated significantly increased IL1-β and AGE staining localized to the insertion and mid-substance of the hyperglycemic tendon.	Thomas et al[35], 2014
Wistar rats	Achilles tendons	CG and DG	DM for 24 d post-induction	Tendon thickness, the density of fibrocytes and total cellularity, blood vessels and mast cells were significantly increased in diabetic tendons compared with non-diabetic tendons. IHC showed increased density of type I collagen, associated with the disorganization of the fibers in the diabetic tendons, and expression of VEGF and NF-κB.	de Oliveira et al[37], 2013
Male diabetic GK rats and Wistar control rats	Achilles tendons	CG and DG	DM for 1 yr	Diabetic tendons exhibited slightly lesser transverse area, but showed no apparent alteration in structural organization of collagen fibers.	Ahmed et al[21], 2012
Male white rats	Achilles tendons	CG and DG	Surgery at two weeks post-induction; four weeks post-surgery.	Fibroblasts, capillary and collagen were reduced during the healing process of diabetic tendons after transection injury.	Sananta et al[44], 2019
Wistar rats	Achilles tendons	CG and DG	Surgery at one-week post-induction; 21 d post-surgery.	The fibroblasts in injured diabetic tendons were significantly increased. IHC of the injured diabetic Achilles tendons showed nearly no Col I expression in comparison with injured non-diabetic tendons.	de Oliveira et al[36], 2019
Wistar rats	Achilles tendons	CG (low fat diet) and DG (high fat diet)	Surgery at 30 d post-induction; days 5, 10 and 15 post-surgery.	The diabetic tendons displayed a significant increase in inflammation and a significant decrease in fibrosis compared to the non-diabetic tendons.	Mohsenifar et al[20], 2014
Male GK rats and control Wistar rats	Achilles tendons	CG and DG	DM for one year; two weeks post-surgery.	After rupture, the diabetic tendons had a reduced reparative activity with decreased transverse area, poor structural organization and decreased vascularity. IHC of injured diabetic tendons showed weaker VEGF, Tβ-4, TGF-β1 and IGF-1immunoreactivity and fewer positively stained tenocytes, but strong COX-2, HIF-1α, iNOS and IL-1β at the injured site compared with injured non-diabetic tendons.	Ahmed et al[45], 2014
Male GK rats and control Wistar rats	Achilles tendons	CG and DG	DM for one year; two weeks post-surgery.	After rupture, the diabetic tendons had a reduced reparative activity illustrated by a much smaller transverse area, poor structural organization with fewer longitudinally oriented collagen fibers along the functional loading axis, and decreased vascularity, compared with injured non-diabetic tendons. Most fibers were yellowish and arranged irregularly, denoting ruptured Col I structures. IHC showed that less Col I, Collagen III and biglycan were observed, but increased MMP-13 around blood vessels and cells in the callus in the healing diabetic tendons.	Ahmed et al[21], 2012
Wistar Albino rats	Achilles tendons	CG and DG	Surgery at 3 d post-induction; 2-, 4- and 6-wk post-surgery.	Although similar collagen deposition and vessels proliferation were observed in both injured diabetic and non-diabetic tendons during healing, the injured diabetic tendons exhibited a significantly smaller amount of fibroblast proliferation and lymphocyte infiltration, and osteochondroid metaplasia of some tenocytes.	Egemen et al[43], 2012

SFTS: Stenosing flexor tenosynovitis; IHC: Immunohistochemical; FDL: Flexor digitorum longus; CG: Control group; DG: Diabetes group; DM: Diabetes mellitus; OPN: Osteopontin; OCN: Osteocalcin; Col II: Collagen II; Col I: Collagen I; TNMD: Tenomodulin; PPARγ: Peroxisome proliferator-activated receptor γ; SD: Sprague-Dawley; AGE: Advanced glycation end-products; VEGF: Vascular endothelial growth factor; GK: Goto-Kakizaki; COX-2: Cyclooxygenase-2; HIF-1α: Hypoxia-inducible factor-1α; iNOS: Inducible nitric oxide synthase; TGF-β: Transforming growth factor beta; IGF: Insulin-like growth factor; MMP: Matrix metalloproteinase; IL-6: Interleukin-6; Tβ: Thymosin β; NOX: NADPH oxidase.