Atp6i deficient mouse model uncovers transforming growth factor-β1/Smad2/3 as a key signaling pathway regulating odontoblast differentiation and tooth root formation

The biomolecular mechanisms that regulate tooth root development and odontoblast differentiation are poorly understood.We found that Atp6i deficient mice(Atp6i^(−/−))arrested tooth root formation,indicated by truncated Hertwig’s epithelial root sheath(HERS)progression.Furthermore,Atp6i deficiency significantly reduced the proliferation and differentiation of radicular odontogenic cells responsible for root formation.Atp6i^(−/−)mice had largely decreased expression of odontoblast differentiation marker gene expression profiles(Col1a1,Nfic,Dspp,and Osx)in the alveolar bone.Atp6i^(−/−)mice sample RNA-seq analysis results showed decreased expression levels of odontoblast markers.Additionally,there was a significant reduction in Smad2/3 activation,inhibiting transforming growth factor-β(TGF-β)signaling in Atp6i^(−/−)odontoblasts.Through treating pulp precursor cells with Atp6i^(−/−)or wild-type OC bone resorption-conditioned medium,we found the latter medium to promote odontoblast differentiation,as shown by increased odontoblast differentiation marker genes expression(Nfic,Dspp,Osx,and Runx2).This increased expression was significantly blocked by anti-TGF-β1 antibody neutralization,whereas odontoblast differentiation and Smad2/3 activation were significantly attenuated by Atp6i^(−/−)OC conditioned medium.Importantly,ectopic TGF-β1 partially rescued root development and root dentin deposition of Atp6i^(−/−)mice tooth germs were transplanted under mouse kidney capsules.Collectively,our novel data shows that the prevention of TGF-β1 release from the alveolar bone matrix due to OC dysfunction may lead to osteopetrosis-associated root formation via impaired radicular odontoblast differentiation.As such,this study uncovers TGF-β1/Smad2/3 as a key signaling pathway regulating odontoblast differentiation and tooth root formation and may contribute to future therapeutic approaches to tooth root regeneration.

Mechanisms of tyrosine kinase inhibitor resistance in renal cell carcinoma

Renal cell carcinoma(RCC),the most prevalent type of kidney cancer,is a significant cause of cancer morbidity and mortality worldwide.Antiangiogenic tyrosine kinase inhibitors(TKls),in combination with immune checkpoint inhibitors(ICls),are among the first-line treatment options for patients with advanced RCC.These therapies target the vascular endothelial growth factor receptor(VEGFR)tyrosine kinase pathway and other kinases crucial to cancer proliferation,survival,and metastasis.TKls have yielded substantial improvements in progression-free survival(PFS)and overall survival(OS)for patients with advanced RCC.However,nearly all patients eventually progress on these drugs as resistance develops.This review provides an overview of TKl resistance in RCC and explores different mechanisms of resistance,including upregulation of alternative proangiogenic pathways,epithelial-mesenchymal transition(EMT),decreased intracellular drug concentrations due to efflux pumps and lysosomal sequestration,alterations in the tumor microenvironment including bone marrow-derived cells(BMDCs)and tumor-associated fibroblasts(TAFs),and genetic factors such as single nucleotide polymorphisms(SNPs).A comprehensive understanding of these mechanisms opens the door to the development of innovative therapeutic approaches that can effectively overcome TKl resistance,thereby improving outcomes for patients with advanced RCC.