Fluconazole-Induced Protein Changes in Osteogenic and Immune Metabolic Pathways of Dental Pulp Mesenchymal Stem Cells of Osteopetrosis Patients.

Abstract

Osteopetrosis is a rare inherited disease caused by osteoclast failure, resulting in increasing bone density in humans. Patients with osteopetrosis possess several dental and cranial complications. Since carbonic anhydrase II (CA-II) deficiency is a major cause of osteopetrosis, CA-II activators might be an attractive potential treatment option for osteopetrosis patients. We conducted comprehensive label-free quantitative proteomics analysis on Fluconazole-treated Dental Pulp Mesenchymal Stem/Stromal Cells from CA-II-Deficient Osteopetrosis Patients. We identified 251 distinct differentially expressed proteins between healthy subjects, as well as untreated and azole-treated derived cells from osteopetrosis patients. Twenty-six (26) of these proteins were closely associated with osteogenesis and osteopetrosis disease. Among them are ATP1A2, CPOX, Ap2 alpha, RAP1B and some members of the RAB protein family. Others include AnnexinA1, 5, PYGL, OSTF1 and PGAM4, all interacting with OSTM1 in the catalytic reactions of HCO3 and the Cl- channel via CAII regulation. In addition, the pro-inflammatory/osteoclast regulatory proteins RACK1, MTSE, STING1, S100A13, ECE1 and TRIM10 are involved. We have identified proteins involved in osteogenic and immune metabolic pathways, including ERK 1/2, phosphatase and ATPase, which opens the door for some CA activators to be used as an alternative drug therapy for osteopetrosis patients. These findings propose that fluconazole might be a potential treatment agent for CAII- deficient OP patients. Altogether, our findings provide a basis for further work to elucidate the clinical utility of azole, a CA activator, as a therapeutic for OP.

• Authors: Zikra Alkhayal, Zakia Shinwari, Ameera Gaafar, Ayodele Alaiya
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 24 Issue 18 (Sep 08 2023) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 37762144 (Publication Type: Journal Article)

Chemical References

• Fluconazole
• Azoles
• RAP1B protein, human
• rap GTP-Binding Proteins

Topics

• Humans
• Fluconazole (pharmacology, therapeutic use)
• Osteogenesis
• Dental Pulp
• Osteopetrosis (drug therapy)
• Azoles
• Metabolic Networks and Pathways
• Mesenchymal Stem Cells
• rap GTP-Binding Proteins