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

Area of Science:

• Molecular Biology
• Cell Biology
• Bone Biology

Background:

• Osteoclast differentiation is critical in osteoporosis pathogenesis, but its regulation is not fully understood.
• Lysine acetyltransferase KAT6A (MYST family) regulates gene expression via histone acetylation.
• Understanding KAT6A's role in osteoclastogenesis is vital for developing osteoporosis treatments.

Purpose of the Study:

• To investigate the role of KAT6A in osteoclast differentiation.
• To elucidate the molecular mechanisms underlying KAT6A's function in this process.
• To assess KAT6A as a potential therapeutic target for osteoporosis.

Main Methods:

• Analyzed KAT6A expression in serum from osteoporosis patients and controls.
• Utilized an ovariectomy (OVX) mouse model and RANKL-induced osteoclast differentiation systems (BMMs, RAW264.7 cells).
• Employed KAT6A knockdown (shRNA) with rescue experiments (TRPV4, Tet1 overexpression) and assessed osteoclast markers (TRAP, c-Fos, NFATc1) and bone parameters (BV/TV, Tb.Th, Tb.N, Tb.Sp).
• Investigated transcriptional regulation using chromatin immunoprecipitation (ChIP) assays.

Main Results:

• KAT6A expression was significantly higher in osteoporosis patients.
• KAT6A knockdown in OVX mice ameliorated bone loss and reduced osteoclast differentiation markers.
• KAT6A directly upregulated Tet1 expression by enhancing H3K9 acetylation and RNA polymerase II recruitment at the Tet1 promoter.
• Tet1 and TRPV4 were identified as key downstream effectors in the KAT6A-mediated osteoclastogenesis pathway.
• Overexpression of Tet1 or TRPV4 rescued KAT6A knockdown-induced inhibition of osteoclast differentiation.

Conclusions:

• KAT6A promotes osteoclast differentiation and contributes to bone loss in osteoporosis.
• The mechanism involves KAT6A-mediated upregulation of Tet1, which subsequently promotes TRPV4 expression.
• This KAT6A-Tet1-TRPV4 regulatory cascade identifies KAT6A as a promising therapeutic target for osteoporosis.