Effects of FGFR Signaling on Cell Proliferation and Differentiation of Apert Dental Cells

Abstract

The Apert syndrome is a rare congenital disorder most often arising from S252W or P253R mutations in fibroblast growth factor receptor (FGFR2). Numerous studies have focused on the regulatory role of Apert FGFR2 signaling in bone formation, whereas its functional role in tooth development is largely unknown. To investigate the role of FGFR signaling in cell proliferation and odontogenic differentiation of human dental cells in vitro, we isolated dental pulp and enamel organ epithelia (EOE) tissues from an Apert patient carrying the S252W FGFR2 mutation. Apert primary pulp and EOE cells were established and shown to exhibit normal morphology and express alkaline phosphatase under differentiation conditions. Similar to control cells, Apert dental pulp and EOE cells expressed all FGFRs, with highest levels of FGFR1 followed by FGFR2 and low levels of FGFR3 and FGFR4. However, Apert cells had increased cell growth compared with control cells. Distinct from previous findings in osteoblast cells, gain-of-function S252W FGFR2 mutation did not upregulate the expression of epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFRα), but elevated extracellular signal-regulated kinase (ERK) signaling in cells after EGF stimulation. Unexpectedly, there was little effect of the S252W mutation on odontogenic gene expression in dental pulp and EOE cells. However, after inhibition of total FGFR signaling or ERK signaling, the expression of odontogenic genes was upregulated in both dental cell types, indicating the negative effect of whole FGFR signaling on odontogenic differentiation. This study provides novel insights on FGFR signaling and a common Apert FGFR2 mutation in the regulation of odontogenic differentiation of dental mesenchymal and epithelial cells.

Pfeiffer syndrome: oral healthcare management and description of new dental findings in a craniosynostosis

“…Interestingly, FGFR‐related signaling pathways are also believed to play essential roles in tooth development . It is not surprising therefore to find dental abnormalities associated with this syndrome.…”

Pectin nanocoating reduces proinflammatory fibroblast response to bacteria

“…FGFR1 is known as a major factor affecting cell proliferation and differentiation. 34 Thus, the enhanced FGFR1 expression in the presence of RG-I could contribute to greater bone regeneration following the P. gingivalis infection. The present study also demonstrated the ability of RG-Is, particularly PA, to suppress the MMP2 expression in the presence of P. gingivalis.…”

“…Recent clinical investigation has demonstrated the important role of the FGF/FGFR signaling in the promotion of bone regeneration. FGFR1 is known as a major factor affecting cell proliferation and differentiation . Thus, the enhanced FGFR1 expression in the presence of RG‐I could contribute to greater bone regeneration following the P. gingivalis infection.…”

Dental approach for Apert syndrome in children: a systematic review

“…In this regard, it has been mentioned that the probability of a second child being affected is 1%, and that a person with AS has a 50% risk of having a child with the syndrome ( 8 ). The FGFR are a family of mitogenic signaling molecules that play an important role on the control of cell proliferation and survival ( 1 ); thus, in AS, fibroblasts are not able to produce the essential fibrous material in several craniofacial tissues, including bone sutures and cartilage, and during tooth formation and regeneration ( 4 , 18 , 20 - 22 ); thus, the mutated FGFR2 gene may influence the dental abnormalities observed in AS ( 21 ).…”