Magnesium Rescues Cystic Fibrosis- and Age-Related Bone Diseases Through an ATF4-Dependent Wnt/β-Catenin Signaling

Bone fragility has emerged as a key clinical manifestation of cystic fibrosis, a genetic disease caused by CFTR mutation, which is not well understood and currently lacks effective therapeutic options. Here we report that CFTR is downregulated in aged wild-type mouse bones; CFTR-deficient mice show early activation of bone cell senescence, abnormal bone micro-architecture, altered osteogenic genes expression and impaired bone fracture healing, mimicking age-related bone disease. We also observed that magnesium ion enters bone cells, activates a transcription factor, ATF4, and promotes Wnt/β-catenin signaling. Magnesium implant improves bone fracture healing in CFTR-mutant mice, which is blocked by Wnt/β-catenin inhibition or ATF4 knockdown. Importantly, oral magnesium or local administration of VX809, a drug that restores CFTR function, improves bone quality in aged wild-type rats/mice. Together, these results collectively show that CFTR-deficiency mimics aging to cause bone defects , while suggesting magnesium supplementation as a possible therapy for CFTR deficiency-associated bone diseases.