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

Area of Science:

• Gerontology
• Orthopedics
• Cell Biology

Background:

• Estrogen-deficiency-driven postmenopausal osteoporosis (PMO) and bone degeneration present challenges with current therapies due to adverse effects.
• Senescent cells (SnCs) and their senescence-associated secretory phenotype (SASP) contribute to age-related diseases.
• Estrogen deficiency in rats leads to a pro-inflammatory microenvironment, accelerated SnC accumulation, and impaired mesenchymal stem cell (MSC) function, driving bone loss.

Purpose of the Study:

• To investigate the efficacy of targeting senescent cells (SnCs) using dasatinib and quercetin (DQ) in treating estrogen-deficiency-induced postmenopausal osteoporosis (PMO).
• To evaluate the impact of DQ therapy on MSC function and osteoporotic bone regeneration.
• To explore the potential of combining DQ with bone morphogenetic protein 2 (BMP2) for enhanced bone repair.

Main Methods:

• Induction of estrogen deficiency in middle-aged rats to model postmenopausal osteoporosis.
• Administration of dasatinib and quercetin (DQ) to target senescent cells (SnCs).
• Assessment of bone microenvironment, MSC function, osteogenic differentiation, and bone regeneration.
• Combination therapy with DQ and bone morphogenetic protein 2 (BMP2).

Main Results:

• Estrogen deficiency induced a pro-inflammatory state with increased SASP and senescent MSCs, leading to bone loss.
• Targeting SnCs with DQ significantly ameliorated PMO and restored MSC function.
• Combined local administration of DQ and BMP2 promoted MSC osteogenic differentiation and improved osteoporotic bone regeneration.

Conclusions:

• Estrogen deficiency-induced bone loss is linked to senescent cell accumulation and a pro-inflammatory microenvironment.
• Dasatinib and quercetin (DQ) effectively target senescent cells, ameliorating PMO and restoring MSC function.
• Repurposing DQ, particularly in combination with BMP2, presents an attractive therapeutic strategy for postmenopausal osteoporosis and related bone diseases.