LepR+ Fibroblasts Activated by BMP Signaling Promote Bone Resorption in Developmental Odontogenic Cysts.

Cystic lesions are more prevalent in jawbones than in other bones. Odontogenic cysts are typically painless and asymptomatic and often reach significant sizes before detection. Unlike odontogenic cysts of inflammatory origin, understanding of the mechanisms of pathogenesis and progression of developmental odontogenic cysts remains incomplete. This study aimed to elucidate the cause and mechanisms of bone resorption in developmental odontogenic cysts. First, single-cell RNA sequencing was conducted for one of the most common developmental odontogenic cysts, dentigerous cysts, and the obtained data were compared with data of dental follicles of embedded teeth. Most differentially expressed genes in dentigerous cysts and dental follicles were associated with immunoglobulin secretion and an activated immunoglobulin-secreting plasma cell subtype was confirmed. Cell-to-cell interaction analysis revealed strong interactions between the activated plasma cells and leptin receptor-expressing (LepR⁺) fibroblasts via "BMP6-BMPR2" interaction. These LepR⁺ fibroblasts constituted the majority of fibroblasts in dentigerous cysts. And these fibroblasts highly expressed genes related to osteoclastogenesis, such as CSF1, IL6, and IL34. Mouse bone marrow-derived monocytes and bone marrow mesenchymal stem cells were treated with culture supernatants of the LepR⁺ fibroblasts. The treatment led to osteoclast formation and bone resorption, and inhibition of BMP signaling suppressed the osteoclastogenesis effect. Thus, the LepR⁺ fibroblasts distinguished developmental odontogenic cysts from benign follicles; such cells interacted with activated plasma cell through the BMP signaling pathway. And the LepR⁺ fibroblasts were crucial in osteoclast induction and bone resorption in dentigerous cysts. This study confirmed a novel LepR⁺ fibroblast-induced bone erosion mechanism in developmental odontogenic cysts, which may inspire future pharmacological or surgical therapies.