Influence of Hedgehog signaling pathway activation on calvarial defect healing in type I diabetic mice
10.12016/j.issn.2096-1456.202550038
- Author:
WU Yingzhang
1
,
2
,
3
,
4
;
LIU Linan
1
,
2
,
3
,
4
;
LIU Shibo
1
,
2
,
3
,
4
;
HU Pei
1
,
2
,
3
,
4
;
LUO En
1
,
2
,
3
,
4
Author Information
1. State Key Laboratory of Oral Diseases &
2. National Center for Stomatology &
3. National Clinical Research Center for Oral Diseases &
4. Department of Orthognathic and TMJ Surgery, West China Hospital of Stomatology, Sichuan University
- Publication Type:Journal Article
- Keywords:
type I diabetes;
high-glucose environment;
Akita mouse model;
cranial defects;
Hedgehog signaling pathway;
Smoothened agonist;
osteocalcin;
osteogenic differentiation
- From:
Journal of Prevention and Treatment for Stomatological Diseases
2025;33(7):542-553
- CountryChina
- Language:Chinese
-
Abstract:
Objective:This study aimed to elucidate the mechanisms underlying the impaired bone healing capacity in type 1 diabetes (T1DM) by investigating the role of the Hedgehog (Hh) signaling pathway in the impaired healing of cranial defects caused by T1DM.
Methods:This study was approved by the experimental animal ethics committee of our hospital. A cranial defect model was established using Akita transgenic mice with spontaneous type I diabetes. The impact of T1DM on osteogenic differentiation and the Hh signaling pathway during cranial defect healing was explored by MicroCT scanning and immunohistochemical (IHC) analysis of osteocalcin (Ocn), Indian Hedgehog (Ihh), Patched1 (Ptch1), and zinc finger protein GLI1 (Gli1). Subsequently, the Hh signaling pathway was activated using smoothened agonist (SAG) (10 mg/kg, gavage), and its potential to improve cranial defect healing in T1DM was assessed by MicroCT and IHC staining. Finally, the ability of SAG (1 000 nmol/L) to counteract the inhibitory effects of a high-glucose environment (25 mol/L) on osteogenic differentiation of mouse bone marrow mesenchymal stem cells (BMSCs) was investigated through in vitro experiments. Detection methods included Alkaline Phosphatase and Alizarin Red staining, as well as quantitative real-time PCR (qPCR) analysis of the osteogenesis-related genes Alp, Spp1, Bglap, and Sp7.
Results:Akita mice exhibited early, stable, and significant spontaneous T1DM characteristics. On postoperative day 21, the newly formed bone in the cranial defect area of Akita mice showed significant decreases in the bone volume-to-tissue volume ratio, volumetric bone mineral density, and Ocn expression (P < 0.05), with significant downregulation of Ihh, Ptch1, and Gli1 (P < 0.05). Activation of the Hh signaling pathway by SAG significantly mitigated the negative impact of T1DM on cranial defect healing in Akita mice (P < 0.05). Moreover, after SAG treatment, the inhibitory effects of the high-glucose environment on the alkaline phosphatase activity and in vitro mineralization capacity of BMSCs were significantly alleviated (P < 0.05), and the expression levels of osteogenic differentiation-related genes were significantly upregulated (P < 0.05).
Conclusion:T1DM inhibits cranial defect healing in Akita mice by suppressing the expression of the Hh signaling pathway, whereas activation of the Hh signaling pathway promotes osteogenesis and ameliorates the inhibitory effects of T1DM on bone healing.
- Full text:2025071014503330982促进Hedgehog信号通路对I型糖尿病小鼠颅骨缺损愈合的影响.pdf
