Chonnam National University study identifies caspase-11 as a key driver of osteoclast genesis

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.

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Reference
DOI: 10.1038/s41418-025-01596-3

About Chonnam National University
Chonnam National University is one of South Korea’s leading public research universities, established in 1952 and headquartered in Gwangju. The university is recognized for its strong programs in medicine, engineering, agriculture, life sciences, and natural sciences. It operates multiple campuses and affiliated hospitals, contributing significantly to research, innovation, and regional development. Chonnam National University collaborates with institutions worldwide and actively participates in international academic exchanges. Known for its commitment to excellence in education and research, the university consistently ranks among South Korea’s prominent higher-education institutions and plays an important role in advancing scientific and technological progress. Website: https://global.jnu.ac.kr/WebApp/web/HOM/COM/Board/board.aspx?boardID=480

About Professor Jeong-Tae Koh
Professor Jeong-Tae Koh is a dentist-scientist at the School of Dentistry, Chonnam National University, whose research focuses on understanding how microbial signals, inflammation, and metabolic diseases drive pathological bone loss and skeletal disorders. His work aims to uncover molecular pathways involved in pathological bone destruction and develop innovative therapeutic strategies for bone-related diseases. He earned his PhD in Pharmacology from Chonnam National University School of Dentistry and completed postdoctoral training at the University of Michigan School of Dentistry. He previously served as Director of the Hard-tissue Biointerface Research Center (MRC).