ZDHHC9-Mediated PKG1 Affects Osteogenesis by Regulating MAMs in T2DM

Area of Science:

• Biochemistry
• Cell Biology
• Biomaterials Science

Background:

• Palmitoylation is a key protein modification impacting cellular functions.
• The role of palmitoylation in peri-implant osteogenesis under type 2 diabetes mellitus (T2DM) is not well understood.

Purpose of the Study:

• To investigate the role of ZDHHC9 in osteoblast dysfunction and peri-implant osteogenesis in T2DM.
• To elucidate the underlying molecular mechanisms involving ZDHHC9, PKG1, and mitochondria-associated endoplasmic reticulum membranes (MAMs).

Main Methods:

• Utilized an in vitro high-glucose model with MC3T3-E1 cells.
• Employed Zdhhc9 knockdown in T2DM mice models.
• Performed co-immunoprecipitation and fluorescence co-localization assays.
• Analyzed endoplasmic reticulum-mitochondria distance and MAMs-related protein expression.

Main Results:

• High glucose inhibited osteoblast proliferation and osteogenesis, with ZDHHC9 upregulation.
• Zdhhc9 knockdown improved osteoblast function and bone healing in T2DM mice.
• ZDHHC9 interacts with PKG1, and PKG1 silencing reversed the benefits of Zdhhc9 knockdown.
• Zdhhc9 and Prkg1 modulation affected ER-mitochondria distance and MAMs.

Conclusions:

• ZDHHC9 exacerbates osteoblast dysfunction in T2DM by palmitoylating PKG1, impacting MAMs.
• ZDHHC9 represents a potential therapeutic target for enhancing peri-implant osteogenesis in diabetic patients.