Spautin-1 inhibits osteoclast differentiation and attenuates bone loss by blocking USP10/JIP1-mediated JNK pathway

Area of Science:

• Biochemistry
• Molecular Biology
• Skeletal Biology

Background:

• Osteoclast hyperactivity drives skeletal disorders like inflammatory bone loss and rheumatoid arthritis.
• The ubiquitin-proteasome system (UPS) critically regulates bone homeostasis and disease.
• Identifying novel therapeutic targets for osteoclast-mediated bone diseases is crucial.

Purpose of the Study:

• To investigate the role of Spautin-1, a ubiquitin-specific protease 10 (USP10) inhibitor, in osteoclastogenesis.
• To elucidate the molecular mechanisms by which Spautin-1 affects osteoclast activity.
• To evaluate the therapeutic potential of Spautin-1 in preclinical models of bone loss.

Main Methods:

• Treatment of bone marrow-derived macrophages (BMMs) with Spautin-1 and RANKL.
• In vitro bone resorption assays.
• Gene expression analysis (USP10, JIP1, NFATc1, osteoclast-related genes).
• Western blotting to assess signaling pathways (JNK, MAPK).
• Murine models of lipopolysaccharide (LPS)-induced bone loss.
• Analysis of patient bone tissues.

Main Results:

• Spautin-1 inhibited RANKL-induced osteoclastogenesis and bone resorption in BMMs.
• Spautin-1 reduced JNK-MAPK signaling and NFATc1 activation by impeding USP10-mediated JIP1 deubiquitination.
• USP10 silencing mimicked Spautin-1 effects, while JIP1 overexpression reversed them.
• Spautin-1 ameliorated LPS-induced bone loss in vivo.
• USP10 and JIP1 expression positively correlated in osteoporotic patient bone tissues.

Conclusions:

• Spautin-1 effectively suppresses osteoclast activity and bone resorption.
• The mechanism involves the USP10-JIP1-JNK pathway, impacting NFATc1 activation.
• Spautin-1 demonstrates therapeutic potential for osteoclast-mediated skeletal disorders.
• USP10 and JIP1 are potential therapeutic targets in osteoporosis.