CARD14-mediated MYC interaction promotes osteoclastogenesis and bone density reduction in adolescent idiopathic scoliosis

Adolescent idiopathic scoliosis (AIS) is characterized by decreased BMD, which is associated with an increased risk of skeletal fragility and poor long-term outcomes. This study explores the role of the Caspase Recruitment Domain Family, Member 14 (CARD14) gene in osteoclast (OC) differentiation and its contribution to bone metabolism dysregulation in AIS patients. RNA sequencing of peripheral blood mononuclear cells (PBMCs) from AIS patients identified significantly elevated CARD14 expression compared to controls. Functional in vitro assays demonstrated enhanced osteoclastogenesis in PBMC-derived cells from AIS patients, as evidenced by an increase in tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and resorption pit formation. To further elucidate CARD14's role, adenoviral vectors were constructed to overexpress CARD14 in BM-derived macrophages from C57/B6 mice, leading to markedly increased OC differentiation and activity. Next, we utilized BM-specific Card14 KO mice to investigate the in vivo role of CARD14. These mice exhibited reduced OC activity, improved trabecular bone microarchitecture, and increased BMD, as evidenced by micro-CT and histological analyses. Additionally, serum biomarkers of bone metabolism further corroborated these findings. Mechanistically, CARD14 was found to interact with Myelocytomatosis viral oncogene homolog (MYC) and regulate OC differentiation through a MYC-dependent pathway, while simultaneously activating NF-κB and MAPK signaling, which are critical for osteoclastogenesis. Adolescent idiopathic scoliosis patients consistently showed lower BMD and higher OC counts than age-matched controls, establishing a link between abnormal OC function and bone loss in AIS. The results highlight that elevated CARD14 expression promotes osteoclastogenesis and bone resorption, contributing to reduced BMD in AIS. Targeting CARD14 and its associated signaling pathways may represent a novel therapeutic approach to address bone density loss in AIS patients, potentially improving their skeletal health and quality of life.