RANKL neutralisation prevents osteoclast activation in a human in vitro ameloblastoma-bone model

Area of Science:

• Oncology
• Biomaterials Science
• Oral and Maxillofacial Surgery

Background:

• Ameloblastoma is a benign jaw neoplasm requiring aggressive surgical resection.
• Current treatments lead to significant patient morbidity.
• Novel therapeutic strategies are needed to target ameloblastoma's microenvironment.

Purpose of the Study:

• To create a humanized 3D disease model of ameloblastoma.
• To investigate the RANKL pathway in the ameloblastoma stromal environment.
• To evaluate the efficacy of denosumab in this model.

Main Methods:

• Engineered in vitro bone using human osteoblasts and collagen type I matrix.
• Differentiated human monocytes into osteoclasts.
• Incorporated ameloblastoma cell lines (AM-1, AM-3) into the 3D model.
• Validated RANKL release via TACE/ADAM17 activation or osteoblast co-culture.

Main Results:

• Successfully generated a 3D humanized model with bone-like nodules and functional osteoclasts.
• Confirmed RANKL release from the tumor microenvironment.
• Denosumab treatment significantly decreased osteoclast activation.

Conclusions:

• The developed 3D model accurately recapitulates ameloblastoma and its stromal interactions.
• Targeting the RANKL pathway with denosumab shows therapeutic potential.
• This model serves as a valuable preclinical platform for testing novel ameloblastoma treatments.