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Repurpose dasatinib and quercetin: Targeting senescent cells ameliorates postmenopausal osteoporosis and rejuvenates bone regeneration.

ABSTRACT: Clinical therapies developed for estrogen-deficiency-driven postmenopausal osteoporosis (PMO) and related diseases, such as bone degeneration, show multiple adverse effects nowadays. Targeting senescent cells (SnCs) and the consequent senescence-associated secretory phenotype (SASP) with a combination of dasatinib and quercetin (DQ) is a recently developed novel therapy for multiple age-related diseases. Herein, we found that estrogen deficiency induced-bone loss was attributed to a pro-inflammatory microenvironment with SASP secretions and accelerated SnC accumulation, especially senescent mesenchymal stem cells (MSCs) characterized by exhaustion and dysfunction in middle aged rats. Systematically targeting SnCs with DQ strikingly ameliorated PMO and restored MSC function. Local administration of DQ and bone morphogenetic protein 2 (BMP2) in combination promoted osteogenic differentiation of MSCs and rejuvenated osteoporotic bone regeneration. Our results repurposed DQ as an attractive therapy for treating PMO and related diseases.

SUBMITTER: Wang Y

PROVIDER: S-EPMC10088057 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Repurpose dasatinib and quercetin: Targeting senescent cells ameliorates postmenopausal osteoporosis and rejuvenates bone regeneration.

Wang Ying Y Che Lingbin L Chen Xi X He Zirui Z Song Dianwen D Yuan Yuan Y Liu Changsheng C

Bioactive materials 20230120

Clinical therapies developed for estrogen-deficiency-driven postmenopausal osteoporosis (PMO) and related diseases, such as bone degeneration, show multiple adverse effects nowadays. Targeting senescent cells (SnCs) and the consequent senescence-associated secretory phenotype (SASP) with a combination of dasatinib and quercetin (DQ) is a recently developed novel therapy for multiple age-related diseases. Herein, we found that estrogen deficiency induced-bone loss was attributed to a pro-inflamma ...[more]

PMID: 37056256

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Project description:BackgroundOsteoporosis (OP), characterized by reduced bone mass and mineral density, is a global metabolic disorder that severely impacts the quality of life in affected individuals. Although current pharmacological treatments are effective, their long-term use is often associated with adverse effects, highlighting the need for safer, more sustainable therapeutic strategies. This study investigates the pro-osteogenic and anti-resorptive potential of the secretome from Smurf1-silenced mesenchymal stem cells (MSCs) as a promising cell-free therapy for bone regeneration.MethodsConditioned media (CM) from Smurf1-silenced rat (rCM-Smur1) and human MSCs (hCM-Smurf1) was collected and analyzed. Pro-osteogenic potential was assessed by measuring in vitro mineralization in human and rat MSCs cultures. In vivo, studies were conducted using a rat ectopic bone formation model and a post-menopausal osteoporotic mouse model. Additionally, primary human osteoporotic MSCs were preconditioned with hCM-Smurf1, and their osteogenic capacity was compared to that induced by BMP2 treatment. Ex vivo, human bone explants were treated with hCM-Smurf1 to assess anti-resorptive effects. Proteomic analysis of the soluble and vesicular CM fractions identified key proteins involved in bone regeneration.ResultsCM from Smurf1-silenced MSCs significantly enhanced mineralization in vitro and bone formation in vivo. Preconditioning human osteoporotic MSCs with hCM-Smurf1 significantly increases in vitro mineralization, with levels comparable to those achieved with BMP2 treatment. Additionally, in ex vivo human bone cultures, treatment with hCM-Smurf1 significantly reduced RANKL expression without affecting OPG levels, indicating an anti-resorptive effect. In vivo, CM from Smurf1-silenced MSCs significantly increased bone formation in a rat ectopic model, and its local administration reduced trabecular bone loss by 50% in a post-menopausal osteoporotic mouse model after a single administration within just four weeks. Proteomic analysis revealed both soluble and vesicular fractions of hCM-Smurf1 were enriched with proteins essential for ossification and extracellular matrix organization, enhancing osteogenic differentiation.ConclusionsThe Smurf1-silenced MSCs' secretome shows potent osteogenic and anti-resorptive effects, significantly enhancing bone formation and reducing bone loss. This study provides compelling evidence for the therapeutic potential of Smurf1-silenced MSC-derived secretome as a non-toxic and targeted treatment for osteoporosis. These findings warrant further in vivo studies and clinical trials to validate its therapeutic efficacy and safety.

Project description:BackgroundSenescent cells, which can release factors that cause inflammation and dysfunction, the senescence-associated secretory phenotype (SASP), accumulate with ageing and at etiological sites in multiple chronic diseases. Senolytics, including the combination of Dasatinib and Quercetin (D + Q), selectively eliminate senescent cells by transiently disabling pro-survival networks that defend them against their own apoptotic environment. In the first clinical trial of senolytics, D + Q improved physical function in patients with idiopathic pulmonary fibrosis (IPF), a fatal senescence-associated disease, but to date, no peer-reviewed study has directly demonstrated that senolytics decrease senescent cells in humans.MethodsIn an open label Phase 1 pilot study, we administered 3 days of oral D 100 mg and Q 1000 mg to subjects with diabetic kidney disease (N = 9; 68·7 ± 3·1 years old; 2 female; BMI:33·9 ± 2·3 kg/m2; eGFR:27·0 ± 2·1 mL/min/1·73m2). Adipose tissue, skin biopsies, and blood were collected before and 11 days after completing senolytic treatment. Senescent cell and macrophage/Langerhans cell markers and circulating SASP factors were assayed.FindingsD + Q reduced adipose tissue senescent cell burden within 11 days, with decreases in p16INK4A-and p21CIP1-expressing cells, cells with senescence-associated β-galactosidase activity, and adipocyte progenitors with limited replicative potential. Adipose tissue macrophages, which are attracted, anchored, and activated by senescent cells, and crown-like structures were decreased. Skin epidermal p16INK4A+ and p21CIP1+ cells were reduced, as were circulating SASP factors, including IL-1α, IL-6, and MMPs-9 and -12.Interpretation"Hit-and-run" treatment with senolytics, which in the case of D + Q have elimination half-lives <11 h, significantly decreases senescent cell burden in humans. FUND: NIH and Foundations. ClinicalTrials.gov Identifier: NCT02848131. Senescence, Frailty, and Mesenchymal Stem Cell Functionality in Chronic Kidney Disease: Effect of Senolytic Agents.

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Repurpose dasatinib and quercetin: Targeting senescent cells ameliorates postmenopausal osteoporosis and rejuvenates bone regeneration.

Publications

Repurpose dasatinib and quercetin: Targeting senescent cells ameliorates postmenopausal osteoporosis and rejuvenates bone regeneration.

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