TTC26 scaffolds MINDY3-mediated RACK1 deubiquitination to drive osteoclastogenesis and pathological bone resorption

Area of Science:

• Bone Biology
• Cell Signaling
• Drug Discovery

Background:

• Osteoclast overactivation drives bone metabolic disorders like osteoporosis.
• Scaffold proteins regulating deubiquitinase (DUB)-substrate interactions are promising therapeutic targets.
• Intraflagellar transport (IFT) proteins, including TTC26, play roles in bone remodeling, but their therapeutic potential is underexplored.

Purpose of the Study:

• To investigate the function of TTC26 in osteoclastogenesis.
• To elucidate the molecular mechanism of TTC26 in regulating osteoclast differentiation.
• To validate TTC26 as a therapeutic target for osteoporosis.

Main Methods:

• Clinical correlation analysis and mouse models (Ttc26flox/flox, Lysm-Cre).
• RNA sequencing, Western blotting, co-immunoprecipitation, and in vitro osteoclast differentiation assays.
• Protein structural analysis and osteoclast-targeted inhibition of Ttc26 in ovariectomized (OVX) mice.

Main Results:

• TTC26 was identified as a novel regulator of osteoclast differentiation.
• TTC26 scaffolds MINDY3 to deubiquitinate RACK1, stabilizing it and activating NFATc1.
• Osteoclast-targeted inhibition of TTC26 alleviated bone loss in OVX mice.

Conclusions:

• TTC26 plays a critical role in bone homeostasis by regulating osteoclastogenesis via the MINDY3-RACK1 axis.
• TTC26 is a potential therapeutic target for osteoporosis and other bone metabolic diseases.
• TTC26 may serve as a biomarker, and its functional residues can guide inhibitor development.