MicroRNA-129 and -335 Promote Diabetic Wound Healing by Inhibiting Sp1-Mediated MMP-9 Expression

Area of Science:

• Molecular Biology
• Dermatology
• Biochemistry

Background:

• Diabetic wounds exhibit impaired healing due to complex molecular mechanisms.
• High matrix metalloproteinase-9 (MMP-9) expression is a key indicator of poor diabetic wound healing.
• The precise regulatory pathways controlling MMP-9 in diabetic wounds remain incompletely understood.

Purpose of the Study:

• To elucidate the regulatory mechanism of MMP-9 in diabetic wound healing.
• To investigate the role of specificity protein-1 (Sp1) and specific microRNAs (miRNAs) in this process.
• To evaluate the therapeutic potential of miR-129 and miR-335 for promoting diabetic wound repair.

Main Methods:

• Investigated the binding of Sp1 to the MMP-9 promoter using molecular assays.
• Assessed the expression levels of miR-129 and miR-335 in diabetic skin tissues.
• Utilized in vitro cell culture models to examine the effects of miRNA overexpression or inhibition on Sp1 and MMP-9.
• Administered miRNA agomirs topically in a diabetic animal model to assess in vivo therapeutic effects.

Main Results:

• Sp1 directly binds to and enhances MMP-9 expression.
• miR-129 and miR-335 directly target Sp1 and are downregulated in diabetic skin.
• Overexpression of miR-129 or miR-335 inhibited Sp1-mediated MMP-9 activity and protein levels.
• Topical application of miR-129 and miR-335 agomirs accelerated diabetic wound healing by reducing MMP-9, enhancing keratinocyte migration, and improving skin structure.
• Combined miRNA treatment showed synergistic effects.

Conclusions:

• Sp1-mediated MMP-9 upregulation is a critical factor in delayed diabetic wound healing.
• miR-129 and miR-335 act as negative regulators of Sp1, thereby controlling MMP-9 expression.
• Therapeutic strategies involving miR-129 and miR-335 hold significant promise for treating impaired wound healing in diabetes.