2. Academic Validation
  3. GDC-0449 suppresses odontogenic keratocyst aggressiveness in fibroblasts by upregulating SPARC via Hedgehog pathway inhibition

GDC-0449 suppresses odontogenic keratocyst aggressiveness in fibroblasts by upregulating SPARC via Hedgehog pathway inhibition

  • Arch Oral Biol. 2025 Aug 13:179:106374. doi: 10.1016/j.archoralbio.2025.106374.
Jiafei Qu 1,  Yongqi Jiang 2,  Shian Wu 3,  Xiwen Chen 4,  Jiemei Zhai 5,  Jing Gao 6,  Yuanzhu Zhou 7,  Yingying Hong 8,  Jing Shen 9,  Defu Chen 10
Affiliations

Affiliations

  • 1 Department of International VIP Dental Clinic, Tianjin Stomatological Hospital, School of Medicine, Nankai University, Tianjin 300041, China; Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, Tianjin 300041, China. Electronic address: 395351867@qq.com.
  • 2 College of Life Sciences, Nankai University, Tianjin 300071, China. Electronic address: jiangyongqi1120@163.com.
  • 3 College of Life Sciences, Nankai University, Tianjin 300071, China. Electronic address: wusa@nankai.edu.cn.
  • 4 College of Life Sciences, Nankai University, Tianjin 300071, China. Electronic address: xiwenchen@nankai.edu.cn.
  • 5 Department of Basic Science, School of Stomatology, Kunming Medical University, Kunming 650500, China. Electronic address: zhaijiemei@qq.com.
  • 6 Department of International VIP Dental Clinic, Tianjin Stomatological Hospital, School of Medicine, Nankai University, Tianjin 300041, China; Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, Tianjin 300041, China. Electronic address: 1034417280@qq.com.
  • 7 Department of International VIP Dental Clinic, Tianjin Stomatological Hospital, School of Medicine, Nankai University, Tianjin 300041, China; Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, Tianjin 300041, China. Electronic address: zhouyuanzhu@tmu.edu.cn.
  • 8 First Clinical Division, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology, Beijing 100081, China. Electronic address: hong_zz@yeah.net.
  • 9 Department of International VIP Dental Clinic, Tianjin Stomatological Hospital, School of Medicine, Nankai University, Tianjin 300041, China; Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, Tianjin 300041, China. Electronic address: shenjing611@163.com.
  • 10 College of Life Sciences, Nankai University, Tianjin 300071, China. Electronic address: chendefu@nankai.edu.cn.
PMID: 40840062 DOI: 10.1016/j.archoralbio.2025.106374
Abstract

Objective: Odontogenic keratocysts (OKCs) are aggressive jaw lesions, either linked to Gorlin-Goltz syndrome or sporadic. We aimed to investigate the impact of the Hedgehog (Hh) pathway inhibitor GDC-0449 on OKC fibroblasts (OKC-Fs). Additionally, we explored whether secreted protein acidic and rich in cysteine (SPARC) was a novel Hh target and its association with OKC aggressiveness.

Design: Fibroblasts from four syndromic and four non-syndromic OKCs were isolated, with patched 1 (PTCH1) mutations found only in syndromic ones. Syndromic OKC-Fs with PTCH1 mutations were treated with GDC-0449, using mutation-free non-syndromic OKC-Fs as controls. Wound healing and transwell assays assessed the migration and invasion of OKC-Fs. Real-time polymerase chain reaction (PCR), Alkaline Phosphatase staining, and tartrate-resistant Acid Phosphatase staining investigated osteogenic differentiation and osteoclastogenic effects. Real-Time PCR and western blotting examined the correlation between SPARC and Hh signaling. SPARC siRNA treatment tested its effect on cell migration and invasion.

Results: GDC-0449 inhibited the migration, invasion, and osteoclastogenic ability, while promoting their osteogenic differentiation of syndromic OKC-Fs. Moreover, GDC-0449 inhibited Hh pathway by decreasing glioma-associated oncogene 1 (GLI1) expression in syndromic OKC-Fs harboring PTCH1 mutations. Additionally, by suppressing Hh pathway, GDC-0449 upregulated SPARC expression, suggesting that Hh-GLI1 signaling exerts a negative regulatory effect on SPARC. Knockdown of SPARC promoted the migration and invasion of OKC-Fs, which could be reversed by GDC-0449.

Conclusion: GDC-0449 suppresses aggressiveness and osteoclastogenesis of OKCs while promoting osteogenesis. GDC-0449 treats OKCs by inhibiting Hh signaling and upregulating SPARC. SPARC could be a potential therapeutic target for OKCs.

Keywords

Hh pathway inhibitor; Invasion; Migration; Odontogenic keratocyst; PTCH1 mutation; SPARC.

Figures
Products
Inhibitors & Agonists
Other Products