USP7 promotes the osteoclast differentiation of CD14+ human peripheral blood monocytes in osteoporosis via HMGB1 deubiquitination

Lin, Youping; Zheng, Guan; Liu, Hua-Tao; Wang, P; Yuan, Weiping; Zhang, Yunhui; Peng, Xiaoshuai; Li, Guojian; Wu, Yanfeng; Shen, Huiyong

doi:10.1016/j.jot.2023.05.007

Cited by 7 publications

(6 citation statements)

References 45 publications

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“…The use of P5091 or P22077, two USP7 inhibitors, display a strong senolytic activity in several models of senescence 31 . While the senolytic activity of P22077 has been confirmed in another study 32 , the activity of P5091 is sometimes associated with pro-senescent drug 33 or senolytic activity.…”

Section: Targeting Senescent Cell Anti-apoptotic Pathways (Scaps)mentioning

confidence: 90%

Senolytics: from pharmacological inhibitors to immunotherapies, a promising future for patients’ treatment

Lelarge,

Capelle,

Oger

et al. 2024

npj Aging

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The involvement of cellular senescence in the initiation and propagation of diseases is clearly characterized, making the elimination of senescent cells essential to treat age-related diseases. The development of senolytic drugs demonstrated that targeting these cells limits the deterioration of patients’ condition, by inducing apoptosis. Nevertheless, the first generations of senolytics which has been developed displayed their activities through specific mechanisms and demonstrated several limitations during clinical development. However, the rational to eliminate senescent cells remains evident, with the necessity to develop specific therapies in a context of diseases and tissues. The evolutions in the field of drug discovery open the way to a new generation of senolytic therapies, such as immunological approaches (CAR-T cells, Antibody-Drug Conjugated or vaccines), which require preliminary steps of research to identify markers specifically expressed on senescent cells, demonstrating promising specific effects. Currently, the preclinical development of these strategies appears more challenging to avoid strong side effects, but the expected results are commensurate with patients’ hopes for treatments. In this review, we highlight the fact that the classical senolytic approach based on drug repurposing display limited efficacy and probably reached its limits in term of clinical development. The recent development of more complex therapies and the extension of interest in the domain of senescence in different fields of research allow to extend the possibility to discover powerful therapies. The future of age-related diseases treatment is linked to the development of new approaches based on cell therapy or immunotherapy to offer the best treatment for patients.

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Section: Targeting Senescent Cell Anti-apoptotic Pathways (Scaps)mentioning

confidence: 90%

Senolytics: from pharmacological inhibitors to immunotherapies, a promising future for patients’ treatment

Lelarge,

Capelle,

Oger

et al. 2024

npj Aging

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“…However, currently there are no studies on applying the senolytic effects of P5091 to age-related osteoporosis and bone healing. It is worth noting that Lin et al found in ovariectomy (OVX)-induced osteoporosis that P5091 exerted its therapeutic effect by inhibiting osteoclast differentiation (25). On the contrary, Xie et al found that USP7 inhibited osteoclast differentiation by stimulating STING, thereby reducing the level of bone loss in the skull (26).…”

Section: Discussionmentioning

confidence: 99%

“…P5091 has been demonstrated to induce apoptosis of tumor cells in various types of cancer, such as colorectal cancer, ovarian cancer, and Ewing sarcoma, by regulating the p53/p21 pathway ( 28, 29 ). While studies have shown that USP7 inhibition could improve OVX-induced osteoporosis by suppressing osteoclast differentiation, the mechanisms underlying bone modeling in the context of aging remain to be investigated ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

USP7 Inhibition Promotes Early Osseointegration in Senile Osteoporotic Mice

Zhou,

Wang,

et al. 2023

Preprint

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SummaryThe interaction between bone mesenchymal stem cells (BMSCs) and macrophages in osteoporosis has gained increasing attention. Aged BMSCs exhibit a senescence-associated secretory phenotype (SASP), which contributes to the inflammatory microenvironment with macrophage inflammaging. USP7, as a key deubiquitinase regulating cellular senescence and inflammation, has been found to promote senolysis when inhibited. We found that USP7 inhibition induced senolysis and osteogenic differentiation in aged BMSCs. For senescent BMDMs, USP7 inhibition suppressed inflammaging and enhanced efferocytosis through EPSIN1/LRP1 pathway, enabling them to efficiently clear apoptotic senescent cells caused by USP7 inhibition. In the femurs and vertebrae of aged mice, it was discovered that USP7 inhibition could rescue bone loss, which may be associated with improved macrophage efferocytosis. This study highlights the potential of USP7 inhibition in promoting senolysis in aged BMSCs and enhancing efferocytosis capacity of senescent BMDMs, which exerts a synergistic therapeutic effect by inducing senescent cell apoptosis and immune clearance.Graphic Abstract

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“…For example, although USP7 is known to regulate osteoclast differentiation, there is still ongoing debate. One group reported that USP7 acts as a positive regulator for osteoclast differentiation through its interaction with high-mobility group protein 1 (HMGB1) [43], while another group proposed that USP7 serves as a negative regulator for osteoclast differentiation via dual effects of attenuating tumor necrosis factor receptor-associated factor 6 (TRAF6)/TAK1 Axis and Stimulating stimulator of interferon gene (STING) Signaling [44]. Meanwhile, USP15 cooperates with charged multivesicular body protein 5 (CHMP5) to stabilize IκBα, resulting in decreased receptor activator of NF-κB ligand (RANKL)-mediated NF-κB activation and osteoclast differentiation [45].…”

Section: Discussionmentioning

confidence: 99%

Deubiquitinase USP17 Regulates Osteoblast Differentiation by Increasing Osterix Protein Stability

Kim,

Piao,

et al. 2023

IJMS

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Deubiquitinases (DUBs) are essential for bone remodeling by regulating the differentiation of osteoblast and osteoclast. USP17 encodes for a deubiquitinating enzyme, specifically known as ubiquitin-specific protease 17, which plays a critical role in regulating protein stability and cellular signaling pathways. However, the role of USP17 during osteoblast differentiation has not been elusive. In this study, we initially investigated whether USP17 could regulate the differentiation of osteoblasts. Moreover, USP17 overexpression experiments were conducted to assess the impact on osteoblast differentiation induced by bone morphogenetic protein 4 (BMP4). The positive effect was confirmed through alkaline phosphatase (ALP) expression and activity studies since ALP is a representative marker of osteoblast differentiation. To confirm this effect, Usp17 knockdown was performed, and its impact on BMP4-induced osteoblast differentiation was examined. As expected, knockdown of Usp17 led to the suppression of both ALP expression and activity. Mechanistically, it was observed that USP17 interacted with Osterix (Osx), which is a key transcription factor involved in osteoblast differentiation. Furthermore, overexpression of USP17 led to an increase in Osx protein levels. Thus, to investigate whether this effect was due to the intrinsic function of USP17 in deubiquitination, protein stabilization experiments and ubiquitination analysis were conducted. An increase in Osx protein levels was attributed to an enhancement in protein stabilization via USP17-mediated deubiquitination. In conclusion, USP17 participates in the deubiquitination of Osx, contributing to its protein stabilization, and ultimately promoting the differentiation of osteoblasts.

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USP7 promotes the osteoclast differentiation of CD14+ human peripheral blood monocytes in osteoporosis via HMGB1 deubiquitination

Cited by 7 publications

References 45 publications

Senolytics: from pharmacological inhibitors to immunotherapies, a promising future for patients’ treatment

Senolytics: from pharmacological inhibitors to immunotherapies, a promising future for patients’ treatment

USP7 Inhibition Promotes Early Osseointegration in Senile Osteoporotic Mice

Deubiquitinase USP17 Regulates Osteoblast Differentiation by Increasing Osterix Protein Stability

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