KAT6A regulates osteoclast differentiation and bone resorption through TET1-mediated TRPV4 expression.

Osteoclast differentiation plays a crucial role in osteoporosis (OP) pathogenesis, yet the regulatory mechanisms remain poorly understood. Lysine acetyltransferase KAT6A, a member of the myeloid-lymphoid or mixed-lineage leukemia (MYST) family, regulates gene expression through histone H3 acetylation. This study investigated the role of KAT6A in osteoclast differentiation and elucidated regulatory mechanisms. Serum samples from osteoporosis patients and healthy controls were analyzed for KAT6A expression. An ovariectomy (OVX) mouse model and receptor activator of nuclear factor kappa-B ligand (RANKL)-induced differentiation system using bone marrow macrophages (BMMs) and RAW264.7 cells were employed. KAT6A knockdown was achieved using short hairpin RNA (shRNA) vectors, with rescue experiments using Transient Receptor Potential Vanilloid 4 (TRPV4) and Tet1 overexpression. Osteoclast differentiation was assessed by tartrate-resistant acid phosphatase (TRAP) staining, phalloidin staining, and osteoclast marker expression analysis (TRAP, c-Fos, NFATc1). Chromatin immunoprecipitation (ChIP) assays were used to investigate transcriptional regulatory mechanisms.KAT6A was significantly elevated in osteoporosis patients compared with controls. In the OVX model, KAT6A knockdown ameliorated bone loss, improving bone volume/total volume (BV/TV), trabecular thickness (Tb.Th), and trabecular number (Tb.N), while reducing trabecular separation (Tb.Sp). KAT6A depletion suppressed osteoclast differentiation markers and reduced TRAP-positive cell formation. Mechanistically, KAT6A directly bound to the Tet1 promoter region, enhancing H3K9 acetylation and RNA polymerase II recruitment, and upregulating Tet1 expression. Tet1 associated with the TRPV4 gene region and appeared to promote its transcription, suggesting potential transcriptional regulation. Overexpression of either Tet1 or TRPV4 rescued the KAT6A knockdown-induced osteoclast differentiation inhibition. KAT6A promotes osteoclast differentiation through a regulatory cascade involving Tet1-mediated TRPV4 upregulation, which identifying KAT6A as a potential therapeutic target for osteoporosis treatment.