METTL3-m6A Promotes FFAR4 Levels in Patients with Endocrine Dysfunctional Osteoporosis Syndrome

Endocrine Dysfunctional Osteoporosis Syndrome (EDOS) is a bone disorder characterized by significant changes in bone microstructure leading to degradation and reduced strength, often resulting in fractures. This research investigates the impact of FFAR4 on individuals suffering from EDOS and elucidates its underlying mechanism.

Samples were gathered from patients diagnosed with EDOS and healthy participants (referred to as "normal") at Taizhou Hospital affiliated with Wenzhou Medical University. Bone Marrow Mesenchymal Stem Cells (BMSCs) and MC3T3-E1 cells were utilized in this investigation. An osteoporosis model was induced in mice through Ovariectomy (OVX).

Elevated levels of serum mRNA expression of FFAR4 were notably observed in individuals with EDOS. Furthermore, a negative correlation was established between serum mRNA expression of FFAR4 and serum ALP or Run2 levels in EDOS patients. The upregulation of FFAR4 mRNA and protein expressions was also observed in mouse models with EDOS. Inhibition of FFAR4 enhanced bone cell growth within the in vitro model and promoted osteogenic differentiation of BMSCs.

Additionally, FFAR4 inhibition was associated with the onset of osteoporosis in the mouse model of EDOS. The stability of FFAR4 was regulated by METTL3-mediated m6A modification. LPA1 emerged as a critical target for FFAR4 in the EDOS model.

Our study suggests that the FFAR4 exacerbates osteoclast differentiation in the EDOS model through the LPA1 axis. FFAR4 is identified as a facilitator of osteoporosis in the development of EDOS, potentially serving as a diagnostic biomarker and therapeutic target for individuals afflicted with this syndrome.