Key Takeaways & Executive Findings
- •• Pyroptosis, a pro-inflammatory programmed cell death, contributes to bone metabolic disorders by releasing inflammatory cytokines that disrupt bone remodeling. • Exercise inhibits pyroptosis through multiple mechanisms, including suppression of NLRP3 inflammasome activation, reduction of pyroptotic protein expression, and modulation of myokine secretion. • Exercise-induced inhibition of pyroptosis leads to decreased osteoclast activity and increased osteoblast activity, thereby improving bone mass and joint health. • Regular exercise represents a promising non-pharmacological strategy for preventing and treating osteoporosis, osteoarthritis, and rheumatoid arthritis by targeting pyroptosis.
Abstract
BACKGROUND: Pyroptosis is extensively involved in bone formation mediated by osteoblasts and bone resorption mediated by osteoclasts. Inflammatory factors released during pyroptosis contribute to bone metabolic imbalance. Exercise can inhibit pyroptosis and regulate the progression of bone metabolic disorders, which has become a research hotspot for preventing and treating such diseases. OBJECTIVE: To summarize the regulatory role of pyroptosis in bone metabolic disorders and to elucidate the molecular mechanisms by which exercise-mediated pyroptosis improves these conditions. METHODS: CNKI and PubMed were searched for relevant literature published from 1992 to 2025. The search terms were “exercise, pyroptosis, osteoporosis, osteoarthritis, rheumatoid arthritis, abnormal bone metabolism, osteoblasts, osteoclasts, bone marrow mesenchymal stem cells, osteocytes, chondrocytes” in Chinese and English, respectively. According to the inclusion and exclusion criteria, 80 articles were included for review. RESULTS AND CONCLUSION: Pyroptosis plays a critical role in the pathogenesis of bone metabolic disorders. Recent studies have indicated that exercise, as a safe and effective non-pharmacological intervention, can alleviate pyroptosis by inhibiting inflammasome activation, suppressing pyroptotic protein expression, modulating myokine secretion, and reducing oxidative stress, thereby decreasing bone resorption and increasing bone formation. However, current research on pyroptosis and bone metabolic disorders has limitations, and the specific pathways and regulatory mechanisms by which exercise-mediated pyroptosis participates in bone metabolic disorders require further investigation.
1. Introduction
Bone metabolic disorders are metabolic diseases caused by an imbalance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation, often leading to physical dysfunction. The dynamic equilibrium between bone formation and resorption constitutes the basis of bone metabolism; any abnormality in either process may contribute to the development and progression of diseases such as osteoporosis, osteoarthritis, and rheumatoid arthritis.
In recent years, pyroptosis, a form of programmed inflammatory cell death, has gained increasing attention for its role in bone metabolic disorders. Pyroptosis activates inflammasomes and promotes the release of pro-inflammatory cytokines such as interleukin-1 and interleukin-18, leading to inflammatory responses and cellular dysfunction in bone tissue. Pyroptosis has been observed in various bone-related cells, including osteoblasts and synovial cells, thereby exacerbating bone resorption and joint destruction. Therefore, inhibiting pyroptosis has become a potential target for regulating bone metabolic disorders.
Exercise intervention can modulate pyroptosis through multiple mechanisms, thereby improving the pathological processes of bone metabolic abnormalities. While pyroptosis-induced inflammation can stimulate immune function, excessive inflammation can aggravate pathological conditions such as rheumatoid arthritis, osteoarthritis, and synovitis. Exercise can inhibit the activation of nuclear factor κB, reduce the activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3), slow the cleavage of caspase-1 to interleukin-1β and interleukin-18, and suppress gasdermin D-mediated pyroptosis, thereby reducing the release of inflammatory factors. Additionally, exercise induces the release of anti-inflammatory cytokines such as interleukin-6, creating an anti-inflammatory environment and reducing oxidative stress, which is beneficial for inhibiting pyroptotic signaling pathways. Furthermore, various cytokines produced during exercise can enhance osteoblast activity and alleviate bone density loss. However, current reviews often focus on the mechanisms of pyroptosis in bone metabolic disorders, while comprehensive reviews on exercise regulating pyroptosis to improve these conditions remain relatively scarce. Therefore, this article reviews the mechanisms of pyroptosis in osteoporosis, osteoarthritis, and rheumatoid arthritis, summarizes the effects of different exercise modalities and intensities on pyroptosis, and discusses the molecular biological mechanisms by which exercise regulates pyroptosis to improve bone metabolic disorders, aiming to provide a reference for exercise intervention in the prevention and treatment of these diseases.
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Zan Junhao, Hu Shujuan, Yuan Xinguo, Pu Rui (2026). Exercise regulation of pyroptosis for the prevention and treatment of bone metabolic disorders. Chinese Journal of Tissue Engineering Research. https://doi.org/10.12307/2026.21326
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Frequently Asked Questions
What is pyroptosis and how does it relate to bone metabolic disorders?
Pyroptosis is a form of programmed inflammatory cell death that triggers the release of pro-inflammatory cytokines such as IL-1β and IL-18. In bone metabolic disorders, pyroptosis in osteoblasts, osteoclasts, and other bone cells disrupts the balance between bone formation and resorption, contributing to conditions like osteoporosis, osteoarthritis, and rheumatoid arthritis.
How does exercise influence pyroptosis in the context of bone health?
Exercise can inhibit pyroptosis through multiple mechanisms, including suppressing NLRP3 inflammasome activation, reducing pyroptotic protein expression (e.g., gasdermin D), modulating myokine secretion, and lowering oxidative stress. These effects help decrease osteoclast activity and increase osteoblast activity, thereby improving bone metabolism.
What are the key molecular pathways involved in exercise-mediated regulation of pyroptosis?
Key pathways include the inhibition of NF-κB signaling, which reduces NLRP3 activation, and the subsequent decrease in caspase-1 cleavage of pro-IL-1β and pro-IL-18. Exercise also promotes anti-inflammatory cytokines like IL-6 and reduces oxidative stress, further suppressing pyroptotic signaling.
Can exercise be considered a therapeutic strategy for bone metabolic disorders?
Yes, exercise is a safe and effective non-pharmacological intervention that can prevent and treat bone metabolic disorders by modulating pyroptosis and improving bone remodeling. It offers a promising adjunctive therapy to conventional treatments.
What are the limitations of current research on exercise and pyroptosis in bone diseases?
Current research is limited by the lack of comprehensive reviews and detailed mechanistic studies. The specific pathways and regulatory mechanisms by which exercise-mediated pyroptosis affects bone metabolic disorders are not fully understood, and more research is needed to establish optimal exercise protocols.
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