Non-pyroptotic caspase-11 activity regulates osteoclastogenesis and pathological bone loss

Area of Science:

• Bone Biology
• Cellular Signaling
• Inflammation and Immunity

Background:

• Osteoclasts are crucial for bone remodeling, but their overactivity causes pathological bone loss.
• While caspases activated by inflammasomes impact osteoclast formation, caspase-11's role beyond pyroptosis is not well understood.

Purpose of the Study:

• To investigate the role of caspase-11 in RANKL-induced osteoclast differentiation and bone resorption.
• To explore the non-inflammatory functions of caspase-11 in osteoclastogenesis.

Main Methods:

• Assessed caspase-11 expression and activity in bone tissues and bone marrow-derived macrophages.
• Utilized caspase-11 knockout mice and in vitro assays with genetic/pharmacological inhibitors.
• Investigated the molecular mechanism involving nuclear translocation and PARP1 cleavage.

Main Results:

• Caspase-11 expression and activity were elevated in conditions of excessive bone resorption.
• Caspase-11 deficiency or inhibition impaired osteoclast differentiation and increased bone mass.
• RANKL-activated caspase-11 cleaves PARP1 in the nucleus, repressing osteoclastogenesis.
• Inhibition of caspase-11 reduced ovariectomy-induced bone loss.

Conclusions:

• Caspase-11 plays a novel, non-inflammatory role in regulating osteoclast differentiation.
• Targeting caspase-11 presents a potential therapeutic strategy for treating osteolytic bone diseases.