Accelerated aging in articular cartilage by ZMPSTE24 deficiency leads to osteoarthritis with impaired metabolic signaling and epigenetic regulation

Abstract

Osteoarthritis (OA) is an age-related degenerative disease without disease-modifying therapy. The lack of aging-induced osteoarthritis models makes the discovery of therapeutic drugs more challenging. The deficiency of ZMPSTE24 could induce Hutchinson–Gilford progeria syndrome (HGPS), a genetic disorder of rapid aging. However, the relationship between HGPS and OA remains unclear. Our results found that the expression of Zmpste24 was decreased in the articular cartilage during the aging process. Zmpste24 knockout mice, Prx1-Cre; Zmpste24fl/fl mice and Col2-CreERT2; Zmpste24fl/fl mice displayed OA phenotype. Loss of Zmpste24 in articular cartilage could exacerbate the occurrence and development of osteoarthritis. Transcriptome sequencing revealed that deletion of Zmpste24 or accumulation of progerin affects chondrocyte metabolism, inhibits cell proliferation and promotes cell senescence. Using this animal model, we elucidate the upregulation of H3K27me3 during chondrocyte senescence and discover the molecular mechanism by which lamin A mutant stabilizes EZH2 expression. The construction of aging-induced osteoarthritis models and the elucidation of the signaling pathways and molecular mechanisms of articular chondrocyte senescence would benefit the discovery and development of new drugs for OA.

Mechanical overloading leads to chondrocyte degeneration and senescence via Zmpste24-mediated nuclear membrane instability

“… 33 Destabilization of the nuclear membrane further leads to changes in heterochromatin distribution, the epigenetic state of histones, and susceptibility to DNA damage. 28 , 34 , 35 , 36 Mu et al. 33 confirmed that Zmpste24 can regulate the rigidity and stiffness of the nuclear membrane and senescence of stem cells, together with the cytoskeleton.…”

“…This is contradictory to our results, which show that the most suitable nuclear membrane stiffness required for different pressure types and functional organs varies, and it is necessary to strengthen or soften nuclear membranes in different mechanical environments to avoid the negative effects of excessive loading on cells. A large number of studies have explored the mechanism of cellular senescence caused by the decreased expression of Zmpste24, such as epigenetic regulation, 28 oxidative stress, 37 pytoprotection 38 and inflammation. 39 In our study, we found that mechanical overloading and subsequent downregulation of Zmpste24 will generate excess ROS and overexpression of Zmpste24 effectively scavenges it, which implicates that anti-oxidative stress may be a potential mechanism under Zmpste24 protection.…”

“… 27 Zmpste24 knockout mice exhibit significant premature aging phenotypes, including spontaneous bone fractures and muscle weakness. In a recent study by Suo et al., 28 Zmpste24 deficiency accelerated cartilage senescence and degeneration. Other studies 29 also suggested that Lamin A and nuclear stability play important roles in the mechanosensation of alveolar cells during mechanical ventilation.…”