New findings show that caspase-11, known for inflammatory signaling, also plays a key role in osteoclast differentiation

JEOLLANAM-DO, South Korea, July 24, 2026 /PRNewswire/ — Millions of people worldwide suffer from osteoporosis, a disease marked by progressive bone loss, weakened skeletal strength, and increased fracture risk. Healthy bone is maintained through continuous remodeling, where osteoblasts build new bone and osteoclasts remove old or damaged bone. Under normal conditions, these processes remain balanced. However, when osteoclast activity becomes excessive, bone resorption outpaces bone formation, leading to osteoporosis and other osteolytic disorders. Current treatments can slow bone loss, but long-term use may have limitations and side effects, highlighting the need for more targeted therapeutic approaches. This requires a deeper understanding of the molecular mechanisms driving pathological bone resorption.

One molecule that has recently gained attention is caspase-11, an inflammatory enzyme best known for its role in innate immunity. It mediates non-canonical inflammasome signaling and pyroptosis, an inflammatory form of programmed cell death triggered during bacterial infection. However, emerging evidence suggests that inflammatory proteins may have functions beyond immune defense. To investigate this, researchers from Chonnam National University, led by Professor Jeong-Tae Koh, studied the role of caspase-11 in osteoclastogenesis and bone loss. The study was published in Volume 33 of Cell Death & Differentiation on October 22, 2025.

The researchers first examined caspase-11 expression in mouse models of excessive bone resorption, including aging, ovariectomy-induced osteoporosis, and periodontitis. They also studied its role in RANKL-induced osteoclast differentiation, which generates bone-resorbing osteoclasts. Using genetic knockout mice, gene-silencing approaches, and the pharmacological inhibitor VX-765, they assessed bone structure via micro-computed tomography and evaluated osteoclast formation and activity through TRAP staining and bone resorption assays. Additional experiments were conducted to elucidate the underlying molecular mechanisms.

Across all models examined, caspase-11 was consistently elevated. During RANKL-induced osteoclastogenesis, it was activated early and proved essential for initiating osteoclast differentiation. Genetic deletion or pharmacological inhibition of caspase-11 significantly reduced osteoclast formation and bone-resorbing activity, while preserving bone mass in vivo. Mechanistically, caspase-11 promoted osteoclastogenesis by translocating to the nucleus and inactivating PARP1, a key suppressor of osteoclast differentiation. Importantly, VX-765 treatment reduced osteoporosis-associated bone loss, highlighting caspase-11 as a potential therapeutic target.

“We discovered that this protein unexpectedly controls bone-destroying cells called osteoclasts, revealing a previously unknown role for an inflammation-associated protein in bone loss. This discovery opens a new direction for developing treatments for diseases characterized by excessive bone destruction, including osteoporosis,” said Professor Koh.

This study uncovers a previously unrecognized role for caspase-11 in bone remodeling, expanding its known functions beyond inflammation and immune defense. “By identifying caspase-11 as a previously unrecognized regulator of bone-resorbing cells, our study provides a foundation for designing more precise therapies that can prevent bone loss by targeting specific disease mechanisms,” shares Professor Koh. The findings also suggest that proteins traditionally associated with immune responses may have important roles in other biological systems.

Overall, the research identifies caspase-11 as a critical regulator of osteoclast differentiation and bone resorption through a mechanism distinct from its established inflammatory functions. By linking caspase-11 to PARP1 inactivation and demonstrating that its inhibition protects against osteoporosis-related bone loss, the study provides a strong foundation for developing more targeted therapies for osteoporosis and other osteolytic diseases.

Reference
Title of original paper: Non-pyroptotic caspase-11 activity regulates osteoclastogenesis and pathological bone loss
Journal: Cell Death & Differentiation
DOI: 10.1038/s41418-025-01596-3

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SOURCE Chonnam National University