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Exogenous Indian hedgehog antagonist damages intervertebral discs homeostasis in adult mice
1War Trauma Medical Center, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical Center, Daping Hospital, Army Medical University, Chongqing, 40038, People's Republic of China.
Background:
Vismodegib, as an exogenous Indian hedgehog (Ihh) antagonist, has been approved by the Food and Drug Administration (FDA) for the clinical treatment of patients with basal cell carcinoma, and previous observations implicate the potential therapeutic of vismodegib in osteoarthritis treatment. However, there is no direct evidence for the role of Ihh signaling in intervertebral discs (IVDs) homeostasis of adult mice. The aim of the present study is to assess the effect of systemic administration of Smoothened inhibitor (SMOi) - vismodegib on IVDs homeostasis during the adult stage.
Methods:
The expression of glioma-associated oncogene homolog 1 (Gli1), the downstream targeting gene of Ihh signaling, in IVDs of adult mice after receiving systemic administration of SMOi was examined by immunohistochemistry. The pathological changes of vertebral bodies after SMOi treatment were evaluated by X-ray and micro-CT. The effects of SMOi on homeostasis of IVDs including cartilaginous endplates (CEP), growth plates (GP) and annulus fibrous (AF) were evaluated by histological analysis. The expressions of Aggrecan, Matrix metalloproteinase 13 (MMP13) and Runt-related transcription factor 2 (Runx2), in IVDs were also investigated by immunohistochemistry. Changes in chondrocyte apoptosis and proliferation in IVDs were evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay and analyzing the expression of the cell proliferation antigen Ki-67.
Results:
Systemic administration of SMOi significantly decreased the expression of Gli1 in IVDs that indicating effective inhibition of Ihh signaling. Bone mass of vertebral bodies was diminished after SMOi treatment. Moreover, IVDs degeneration (IDD) like defects including CEP sclerosis, degenerative nucleus pulposus (NP) and fissure within AF, as well as narrowed or fused GP and loss bone mass of vertebral bodies was observed in SMOi-treated mice. The severity of IDD was time-dependent with the administration of SMOi treatment after 2-8 weeks. The expressions of Aggrecan, MMP13 and Runx2 in IVDs of mice receiving SMOi treatment were significantly decreased. In addition, chondrocyte apoptosis was significantly enhanced, while chondrocyte proliferation was significantly inhibited.
Conclusions:
Our study propose that systemic administration of vismodegib damages IVDs homeostasis via inhibition of Ihh signaling in adult mice. The clinical application of Ihh signaling antagonists such as vismodegib should be careful considering these side adverse.
The Translational Potential Of This Article:
Vismodegib as an exogenous antagonist of Ihh signaling has been approved by the FDA for the clinical treatment of patients with basal cell carcinoma. However, it is still unknown whether vismodegib will has adverse effects on the patient or animal model of IVDs cartilage homeostasis. Based on our study, systemic administration of vismodegib damages IVDs homeostasis via inhibition of Ihh signaling in adult mice and special attention should be paid to the clinical application of vismodegib.
Insights
Systemic administration of vismodegib, an Indian hedgehog (Ihh) signaling inhibitor, damages intervertebral disc (IVD) homeostasis in adult mice. This highlights potential adverse effects of vismodegib on IVD health.
Area of Science:
- Biomedical research
- Skeletal biology
- Pharmacology
Background:
- Vismodegib, an Indian hedgehog (Ihh) antagonist, is FDA-approved for basal cell carcinoma.
- Previous studies suggest vismodegib's potential in osteoarthritis treatment.
- The role of Ihh signaling in adult intervertebral disc (IVD) homeostasis remains uncharacterized.
Purpose of the Study:
- To investigate the effect of systemic administration of vismodegib, a Smoothened inhibitor (SMOi), on IVD homeostasis in adult mice.
- To assess the impact of Ihh signaling inhibition on the structural and cellular integrity of IVDs.
Main Methods:
- Systemic administration of SMOi (vismodegib) to adult mice.
- Immunohistochemistry to evaluate Glioma-associated oncogene homolog 1 (Gli1) expression.
- X-ray and micro-CT for vertebral body pathology assessment.
- Histological analysis of IVDs (cartilaginous endplates, growth plates, annulus fibrosus).
- Assessment of Aggrecan, Matrix metalloproteinase 13 (MMP13), and Runt-related transcription factor 2 (Runx2) expression.
- Evaluation of chondrocyte apoptosis and proliferation using TUNEL assay and Ki-67 staining.
Main Results:
- SMOi administration effectively inhibited Ihh signaling, evidenced by decreased Gli1 expression in IVDs.
- Significant IVD degeneration was observed, including CEP sclerosis, NP degeneration, AF fissures, and GP abnormalities.
- Vertebral bone mass was diminished, and the severity of IVD degeneration was time-dependent.
- Expressions of Aggrecan, MMP13, and Runx2 were significantly reduced in treated IVDs.
- Chondrocyte apoptosis increased, while proliferation decreased.
Conclusions:
- Systemic administration of vismodegib impairs IVD homeostasis in adult mice by inhibiting Ihh signaling.
- Clinical use of Ihh signaling antagonists like vismodegib requires caution due to potential adverse effects on IVDs.
- Further research is needed to understand the long-term consequences and clinical implications of vismodegib on spinal health.
