TGF-β3 Regulates Adhesion Formation Through the JNK/c-Jun Pathway During Flexor Tendon Healing

Abstract Background: The injured flexor tendon has poor healing ability, 15 which is easy to cause tendon adhesion. It can affect the recovery of tendon function, which is still a long term and difficult task for surgeons. Transforming growth factor β (TGF-β) has been widely considered to play an important role in flexor tendon repair in recent years. Aim: This work was to investigate the anti-adhesion and anti-inflammatory effects of TGF-β3 on flex or digitorum longus (FDL) tendon repair rats. Method: Anastomosis models of tendon laceration in the flexion toes of rats were delivered with no treatment, vehicle or TGF-β3 - overexpressed adenovirus vector (ad-TGF-β3) locally to the injured tendon area from day 3 to 8. Subsequently, the expression of TGF-β3, TGF-β1/2, Smad3, Smad7, JNK, phosphorylation (p)-JNK, c-Jun and phosphorylation (p)-c-Jun were detected by western blot, the expression of Mmp9 and Mmp2 by RT-qPCR, the Range of motion (ROM) and sliding resistance by adhesion formation testing, the mechanical strength of tendon healing by biomechanical testing, the pathologic changes of flexor tendon tissues by HE staining, the expression of collagen type III by immunohistochemical staining, and the levels of IL-6, TNF-α, COX2 and IL-1β in serum by ELISA, respectively. Results: Rat models treated with no treatment showed a lower elevation of TGF-β3 and Smad7 expression, and a higher elevation of TGF-β1/2 and Smad3 expression, during day 14 to day 28. Besides, under the treatment of ad-TGF-β3, significantly increase was reflected in the expression of TGF-β3 and Smad7, ROM, as well as mechanical strength of flexor tendon, whereas significantly reduction was shown in sliding resistance, content of inflammatory cytokines, ratio of p-JNK/JNK, p-c-Jun/c-Jun, as well as the expression of TGF-β1/2, Smad3, Mmp9 and Mmp2 genes, as compared to those from vehicle treatment. Meanwhile, TGF-β3 demonstrated better pathologic recovery process with no obvious necrosis or fracture of collagen fibers. Besides, TGF-β3 revealed a significant reduction of collagen type-III expression in the flexor tendon healing tissues. Conclusion: These findings suggested that TGF-β3 effectively protected against flexor tendon injury via regulating adhesion formation.

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TGF-β3 regulates adhesion formation through the JNK/c-Jun pathway during flexor tendon healing

BMC Musculoskeletal Disorders ◽

10.1186/s12891-021-04691-x ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Ke Jiang ◽

Yuling Li ◽

Chao Xiang ◽

Yan Xiong ◽

Jiameng Jia

Keyword(s):

Mechanical Strength ◽

Collagen Type ◽

Transforming Growth Factor ◽

Flexor Tendon ◽

Adhesion Formation ◽

Tendon Repair ◽

Tendon Healing ◽

Collagen Type Iii ◽

Type Iii ◽

Tgf Β1

Abstract Background The injured flexor tendon has poor healing ability, which is easy to cause tendon adhesion. It can affect the recovery of tendon function, which is still a long-term and difficult task for surgeons. Transforming growth factor β (TGF-β) has been widely considered to play an important role in flexor tendon repair in recent years. Aim This work was to investigate the anti-adhesion and anti-inflammatory effects of TGF-β3 on flexor digitorum longus (FDL) tendon repair rats. Method Anastomosis models of tendon laceration in the flexion toes of rats were delivered with no treatment, vehicle, or TGF-β3 -overexpressed adenovirus vector (ad-TGF-β3) locally to the injured tendon area from day 3 to 8. Subsequently, the expression of TGF-β3, TGF-β1/2, Smad3, Smad7, JNK, phosphorylation (p)-JNK, c-Jun, and phosphorylation (p)-c-Jun were detected by western blot, the expression of Mmp9 and Mmp2 by RT-qPCR, the Range of motion (ROM) and gliding resistance by adhesion formation testing, the mechanical strength of tendon healing by biomechanical testing, the pathologic changes of flexor tendon tissues by HE staining, the expression of collagen type III by immunohistochemical staining, and the levels of IL-6, TNF-α, COX2 and IL-1β in serum by ELISA, respectively. Results Rat models treated with no treatment showed a lower elevation of TGF-β3 and Smad7 expression, and a higher elevation of TGF-β1/2 and Smad3 expression, during day 14 to day 28. Besides, under the treatment of ad-TGF-β3, a significantly increase was reflected in the expression of TGF-β3 and Smad7, ROM, as well as mechanical strength of flexor tendon, whereas significantly reduction was shown in gliding resistance, the content of inflammatory cytokines, the ratio of p-JNK/JNK, p-c-Jun/c-Jun, as well as the expression of TGF-β1/2, Smad3, Mmp9, and Mmp2 genes, as compared to those from vehicle treatment. Meanwhile, TGF-β3 demonstrated a better pathologic recovery process with no obvious necrosis or fracture of collagen fibers. Besides, TGF-β3 revealed a significant reduction of collagen type-III expression in the flexor tendon healing tissues. Conclusion These findings suggested that TGF-β3 effectively protected against flexor tendon injury via regulating adhesion formation.

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The role of thrombospondin-1-mediated TGF-β1 on collagen type III synthesis induced by high glucose

Molecular and Cellular Biochemistry ◽

10.1007/s11010-010-0590-7 ◽

2010 ◽

Vol 346 (1-2) ◽

pp. 49-56 ◽

Cited By ~ 15

Author(s):

Mengxiong Tang ◽

Fenghua Zhou ◽

Wei Zhang ◽

Zhongxiu Guo ◽

Yuanyuan Shang ◽

...

Keyword(s):

High Glucose ◽

Collagen Type ◽

Collagen Type Iii ◽

Type Iii ◽

Thrombospondin 1 ◽

Tgf Β1

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Glucose-induced fibronectin and collagen type III expression in renal fibroblasts can occur independent of TGF-β1

Kidney International ◽

10.1046/j.1523-1755.2003.00824.x ◽

2003 ◽

Vol 63 (3) ◽

pp. 878-888 ◽

Cited By ~ 29

Author(s):

Suzanne Lam ◽

Nicole A.M. Verhagen ◽

Frank Strutz ◽

Johan W. van der Pijl ◽

Mohamed R. Daha ◽

...

Keyword(s):

Collagen Type ◽

Collagen Type Iii ◽

Type Iii ◽

Tgf Β1

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Synthesis and Formulation of Four-Arm PolyDMAEA-siRNA Polyplex for Transient Downregulation of Collagen Type III Gene Expression in TGF-β1 Stimulated Tenocyte Culture

ACS Omega ◽

10.1021/acsomega.9b03216 ◽

2020 ◽

Vol 5 (3) ◽

pp. 1496-1505 ◽

Cited By ~ 1

Author(s):

Xin Liao ◽

Noelia D Falcon ◽

Ali A Mohammed ◽

Yasmin Z. Paterson ◽

Andrew Geoffrey Mayes ◽

...

Keyword(s):

Gene Expression ◽

Collagen Type ◽

Collagen Type Iii ◽

Type Iii ◽

Tgf Β1

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The Effect of Seprafilm on Adhesion Formation and Tendon Healing After Flexor Tendon Repair in Chicken

Orthopedics ◽

10.3928/01477447-20100129-16 ◽

2010 ◽

Vol 33 (3) ◽

pp. 164-170 ◽

Cited By ~ 10

Author(s):

Erhan Yilmaz ◽

Mustafa Avci ◽

Mehmet Bulut ◽

Halidun Kelestimur ◽

Lokman Karakurt ◽

...

Keyword(s):

Flexor Tendon ◽

Adhesion Formation ◽

Tendon Repair ◽

Tendon Healing ◽

Flexor Tendon Repair

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THE EFFECT OF THERMAL PRECONDITIONING OF THE LIMB ON FLEXOR TENDON HEALING

Journal of Hand Surgery (European Volume) ◽

10.1016/j.jhsb.2007.01.004 ◽

2007 ◽

Vol 32 (3) ◽

pp. 289-295 ◽

Cited By ~ 3

Author(s):

C. HEALY ◽

K. J. MULHALL ◽

D. FITZ PATRICK ◽

E. W. KAY ◽

D. BOUCHIER-HAYES

Keyword(s):

Heat Shock ◽

Flexor Tendon ◽

Adhesion Formation ◽

Rabbit Model ◽

Tendon Repair ◽

Tendon Healing ◽

Flexor Tendon Repair ◽

Treatment Groups ◽

Tendon Surgery ◽

Thermal Preconditioning

Thermal preconditioning reduces inflammation by inducing cytoprotective heat shock proteins. We evaluated the role of limb thermal preconditioning in a rabbit model of flexor tendon repair. The treatment groups underwent limb preconditioning by elevating the limb temperature to 41.5 °C for 20 minutes. The animals were sacrificed three and six weeks after flexor tendon repair. Heat shock protein72 expression of the treated limb was measured at 18 hours. Macroscopic analysis demonstrated a significant decrease in adhesion formation in the three week treatment group. The inflammatory infiltrate was significantly reduced for both treatment groups. The difference in ultimate tensile strength was not significant. We conclude that thermal preconditioning of the limb before flexor tendon repair decreases inflammation and adhesion formation in a rabbit model and has the potential to improve clinical outcome of flexor tendon surgery.

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The Effect of Pulsed Electromagnetic Fields on Flexor Tendon Healing In the Rabbit

Journal of Hand Surgery (European Volume) ◽

10.1016/s0266-7681(96)80198-7 ◽

1996 ◽

Vol 21 (6) ◽

pp. 808-812 ◽

Cited By ~ 23

Author(s):

C. G. GREENOUGH

Keyword(s):

Electromagnetic Fields ◽

Flexor Tendon ◽

Controlled Trial ◽

Adhesion Formation ◽

Tendon Repair ◽

Tendon Healing ◽

Pulsed Electromagnetic Fields ◽

Double Blind ◽

Vessel Growth ◽

Pulsed Electromagnetic

A double-blind controlled trial of the effects of pulsed electromagnetic fields on flexor tendon healing in adult New Zealand White rabbits was performed. A pulse burst waveform, previously demonstrated to influence new vessel growth in the rabbit, was employed. No significant effect was observed on either the healed strength of the tendon repair or the adhesion formation between the repair and the surrounding tissues. The model used for examination of adhesion formation was reproducible and is recommended for further work on the adhesion formation of healing tendons.

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