Bone-targeted delivery of senolytics to eliminate senescent cells increases bone formation in senile osteoporosis

Xing, Xiaotao; Tang, Qi; Zou, Jiaojiao; Huang, He; Yang, Jian; Gao, Xin; Xu, Xun; Ma, Shixing; Li, Maojiao; Cheng, Liang; Tan, Lin; Liao, Li; Tian, Weidong

doi:10.1016/j.actbio.2022.11.056

Cited by 20 publications

(10 citation statements)

References 47 publications

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“…For this developed bone-targeting delivery, we utilized the (AspSerSer) 6 as the bonetargeting moiety, which has been well-validated in our previous study. [23,29] In addition, we use macrophage-derived sEVs as the drug nano-carriers. As a type of natural organelles secreted by cells, these sEVs are explored as drug delivery vehicles with minimal immune response.…”

Section: Discussionmentioning

confidence: 99%

“…(AspSerSer) 6 , an oligopeptide of six repeats of Asp-Ser-Ser, has high affinity for bone tissue and is widely used as bone-targeting moiety in the research of osteoporosis, bone and joint disease, osteomyelitis, multiple myeloma, bone metastasis cancer, skull defect, and other orthopaedic diseases. [20,21,23] To evaluate the bone-targeting capacity of (AspSerSer) 6 -sEVs/DM1-Gal, the Dir-labeled (AspSerSer) 6 -sEVs/DM1-Gal and sEVs/DM1 were respectively intravenously injected into the 20-month-old mice to explore theirs in vivo bio-distribution. The ex vivo fluorescent imaging of bone and other major tissues including liver, heart, spleen, lung, and kidney were harvested at 4 and 24 h after injection.…”

Section: Dm1-gal Was Encapsulated In (Aspserser) 6 -Sevs Nanoparticle...mentioning

confidence: 99%

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Elimination of Senescent Osteocytes by Bone‐Targeting Delivery of β‐Galactose‐Modified Maytansinoid Prevents Age‐Related Bone Loss

He,

Zhang,

Chen

et al. 2023

Adv Healthcare Materials

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The accumulation of senescent cells in bone during aging contributes to senile osteoporosis, and clearance of senescent cells by senolytics could effectively alleviate bone loss. However, the applications of senolytics are limited due to their potential toxicities. Herein, small extracellular vesicles (sEVs) have been modified by incorporating bone‐targeting peptide, specifically (AspSerSer)6, to encapsulate galactose‐modified Maytansinoids (DM1). These modified vesicles are referred to as (AspSerSer)6‐sEVs/DM1‐Gal, and they have been designed to specifically clear the senescent osteocytes in bone tissue. In addition, the elevated activity of lysosomal β‐galactosidase in senescent osteocytes, but not normal cells in bone tissue, could break down DM1‐Gal to release free DM1 for selective elimination of senescent osteocytes. Mechanically, DM1 could disrupt tubulin polymerization, subsequently inducing senescent osteocytes apoptosis. Further, administration of bone‐targeting senolytics to aged mice could alleviate aged‐related bone loss without non‐obvious toxicity. Overall, this bone‐targeting senolytics could act as a novel candidate for specific clearance of senescent osteocytes, ameliorating age‐related bone loss, with a promising therapeutic potential for senile osteoporosis.

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Section: Discussionmentioning

confidence: 99%

Section: Dm1-gal Was Encapsulated In (Aspserser) 6 -Sevs Nanoparticle...mentioning

confidence: 99%

Elimination of Senescent Osteocytes by Bone‐Targeting Delivery of β‐Galactose‐Modified Maytansinoid Prevents Age‐Related Bone Loss

He,

Zhang,

Chen

et al. 2023

Adv Healthcare Materials

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“…[ 41 ] Translation to human models has remained difficult, and even in animal models due to high incidence of premature death. Despite this, there is growing evidence that targeting senescent cell populations for removal (senolytics) could be a promising therapeutic target for prevention of aging‐induced bone diseases [ 42 ] ( Figure 1 ).…”

Section: Basic Pathology Of Aging Bone and Its Reduced Regenerative P...mentioning

confidence: 99%

“…Xing and co‐workers also used another approach for targeted delivery of quercetin in vivo via use of a bone‐targeting liposome delivery system. [ 42 ] As compared to systemic intraperitoneal injection of drug, quercetin‐loaded liposomes were significantly more effective at selectively eliminating senescent cells in mice, leading to improved osteogenic activity in a senile mouse osteoporosis model.…”

Section: Modulating Cellular Senescence In Bonementioning

confidence: 99%

Biomimetic Therapeutics for Bone Regeneration: A Perspective on Antiaging Strategies

Miszuk,

Sun

2023

Macromolecular Bioscience

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Advances in modern medicine and the significant reduction in infant mortality have steadily increased the population's lifespan. As more and more people in the world grow older, incidence of chronic, noncommunicable disease is anticipated to drastically increase. Recent studies have shown that improving the health of the aging population is anticipated to provide the most cost‐effective and impactful improvement in quality of life during aging‐driven disease. In bone, aging is tightly linked to increased risk of fracture, and markedly decreased regenerative potential, deeming it critical to develop therapeutics to improve aging‐driven bone regeneration. Biomimetics offer a cost‐effective method in regenerative therapeutics for bone, where there are numerous innovations improving outcomes in young models, but adapting biomimetics to aged models is still a challenge. Chronic inflammation, accumulation of reactive oxygen species, and cellular senescence are among three of the more unique challenges facing aging‐induced defect repair. This review dissects many of the innovative biomimetic approaches research groups have taken to tackle these challenges, and discusses the further uncertainties that need to be addressed to push the field further. Through these research innovations, it can be noted that biomimetic therapeutics hold great potential for the future of aging‐complicated defect repair.

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“…Current strategies to maintain BMSCs self-renewal and differentiation potential include utilization of growth factors, drugs, extracellular vesicles etc. to alter the cell culture microenvironment [46][47][48]. Herein, a previously optimized osteoinductive extracellular vesicles derived from young BMSCs was introduced and its effect on O-BMSCs was explored in the following experiments.…”

Section: Proliferation and Osteogenic Capacity Was Decreased In Senes...mentioning

confidence: 99%

Young BMSC-derived extracellular vesicles containing lncRNA sponging miR-1843a-5p to regulate Mob3a/YAP axis promote osteogenesis of senescent BMSCs

Qi,

Pan,

Yan

et al. 2023

Preprint

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Bone repair in elderly patients poses a huge challenge due to the age-related progressive degenerative decline in regenerative abilities attributed to the senescence of bone marrow stem cells (BMSCs). Stem cell extracellular vesicles-mediated therapy are increasingly acknowledged as a promising strategy for delaying senescence and promoting osteogenesis. Osteoinductive exosome (OI-exo) derived from young BMSCs was applied to treatment of aging bone regeneration and demonstrated to alleviate aging-related phenotypes and promote proliferation and osteogenic differentiation of senescent BMSCs in vitro. OI-exo-loaded hierarchical mesoporous bioactive glass (MBG) scaffold was applied in calvarial defect of aged rats and induced rapid bone formation and efficient enhancement in osteogenesis in vivo, though excess activity of bone resorption in senescent individuals remained a tremendous challenge in aged bone regeneration. The potential underlying mechanism of young extracellular vesicles-enhanced osteogenesis of old BMSCs was revealed that OI-exos were rich in lncRNA-ENSRNOG00000056625, which functioned as a promoter of YAP dephosphorylation and nuclear translocation, ultimately resulting in elevated proliferation and osteogenic differentiation and reduced senescence-related phenotypes. The findings herein revealed the competing endogenous RNA network lncRNA-ENSRNOG00000056625/miR-1843a-5p/Mob3a, and might provide novel insights into the extracellular vesicles-stimulated osteogenesis and the downstream YAP signaling as a potential critical pathway in aging bone regeneration.

show abstract

Bone-targeted delivery of senolytics to eliminate senescent cells increases bone formation in senile osteoporosis

Cited by 20 publications

References 47 publications

Elimination of Senescent Osteocytes by Bone‐Targeting Delivery of β‐Galactose‐Modified Maytansinoid Prevents Age‐Related Bone Loss

Elimination of Senescent Osteocytes by Bone‐Targeting Delivery of β‐Galactose‐Modified Maytansinoid Prevents Age‐Related Bone Loss

Biomimetic Therapeutics for Bone Regeneration: A Perspective on Antiaging Strategies

Young BMSC-derived extracellular vesicles containing lncRNA sponging miR-1843a-5p to regulate Mob3a/YAP axis promote osteogenesis of senescent BMSCs

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