Pyroptosis mediates osteoporosis via the inflammation immune microenvironment

Abstract

Osteoporosis represents a systemic imbalance in bone metabolism, augmenting the susceptibility to fractures among patients and emerging as a notable mortality determinant in the elderly population. It has evolved into a worldwide concern impacting the physical well-being of the elderly, imposing a substantial burden on both human society and the economy. Presently, the precise pathogenesis of osteoporosis remains inadequately characterized and necessitates further exploration. The advancement of osteoporosis is typically linked to the initiation of an inflammatory response. Cells in an inflammatory environment can cause inflammatory death including pyroptosis. Pyroptosis is a recently identified form of programmed cell death with inflammatory properties, mediated by the caspase and gasdermin families. It is regarded as the most inflammatory form of cell death in contemporary medical research. Under the influence of diverse cytokines, macrophages, and other immune cells may undergo pyroptosis, releasing inflammatory factors, such as IL-1β and IL-18. Numerous lines of evidence highlight the pivotal role of pyroptosis in the pathogenesis of inflammatory diseases, including cancer, intestinal disorders, hepatic conditions, and cutaneous ailments. Osteoporosis progression is frequently associated with inflammation; hence, pyroptosis may also play a role in the pathogenesis of osteoporosis to a certain extent, making it a potential target for treatment. This paper has provided a comprehensive summary of pertinent research concerning pyroptosis and its impact on osteoporosis. The notion proposing that pyroptosis mediates osteoporosis via the inflammatory immune microenvironment is advanced, and we subsequently investigate potential targets for treating osteoporosis through the modulation of pyroptosis.

Keywords: bone metabolism; inflammatory factor; inflammatory immune microenvironment; osteoporosis; pyroptosis.

Figure 1

Under the condition of estrogen deficiency, alterations occur in the immune microenvironment within bone tissue. Immune cells, together with the inflammatory factors they release, establish an enduring chronic inflammatory microenvironment. This disturbance in bone metabolism disrupts the equilibrium, leading to a compounded effect of increased bone resorption and reduced bone synthesis, ultimately culminating in osteoporosis.

Figure 2

Pyroptosis can be categorized into canonical, non-canonical, and other pathways. In the canonical pathway, PRRs get activated by multiple signals, transduced by NF-κB signaling to form the inflammasome. Caspase-1 cleaves GSDMD to create the plasma membrane pore, and IL-18 and IL-1β are also cleaved by caspase-1 into active forms for release into the extracellular space, ultimately leading to pyroptosis. In the non-classical pathway, caspase-4/5/11 can be directly activated by LPS and undergo pyroptosis by directly cleaving GSDMD. Other gasdermin pyroptosis pathways mediated by caspase-3/8, granzyme A, and SpeB are also identified.

Figure 3

During the progression of osteoporosis, pyroptosis may occur in both immune cells and bone-metabolizing cells. Following pyroptosis, inflammatory factors are released into the bone marrow cavity, giving rise to a chronic inflammatory immune microenvironment. Within this microenvironment, the homeostasis of bone metabolism is perturbed, ultimately contributing to osteoporosis by amplifying bone resorption and diminishing bone synthesis. Consequently, the inhibition of pyroptosis is anticipated to emerge as a therapeutic target for the treatment of osteoporosis.