Rapamycin impairs bone accrual in young adult mice independent of Nrf2

Martin, Stephen A.; Riordan, Ruben; Wang, Rong; Yu, Zhen; Aguirre-Burk, Allan M.; Wong, Carmen P.; Olson, Dawn A.; Branscum, Adam J.; Turner, Russell T.; Iwaniec, Urszula T.; Pérez, Viviana

doi:10.1016/j.exger.2021.111516

Cited by 7 publications

(7 citation statements)

References 52 publications

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“… 27–30 The results of studies examining the in vivo impact of rapamycin treatment on skeletal health have been equivocal. We previously demonstrated rapamycin treatment impaired bone accrual in young female mice, 31 and our results are supported by similar findings of impaired skeletal growth in other studies utilizing young animals. 32 , 33 In contrast, in rodent models of senile, ovariectomy-induced, and high turnover–induced osteoporosis, rapamycin, and rapamycin analogs suppressed trabecular bone loss.…”

Section: Introductionsupporting

confidence: 91%

“…In young, wild-type animals that are growing or have just reached skeletal maturity, rapamycin tends to retard bone growth and accrual, induce bone loss, and dysregulate growth plate dynamics, likely through inhibition/antagonism of anabolic signaling pathways (eg, insulin, IGF-1, growth hormone). 31–33 Alternatively, only 2 studies have examined the impact of rapamycin on the skeleton of aged animals and, in contrast to our work presented here, both studies have demonstrated geroprotective effects of rapamycin. Luo et al.…”

Section: Discussioncontrasting

confidence: 63%

“…We previously reported rapamycin treatment at a dosage of 4 mg/kg, given via intraperitoneal injection every other day, for a duration of 12 wk, was detrimental to the skeleton of 8-wk-old female mice. 31 We speculated that these effects were due to the young age at which rapamycin was initiated and/or the dosing regimen inducing potential mTORC2 inhibition in bone cells. mTORC2 inhibition could have impacted the skeleton either directly via alterations in bone cell dynamics regulated by mTORC2 or indirectly via systemic perturbations such as impaired glucoregulation.…”

Section: Discussionmentioning

confidence: 99%

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Rapamycin does not alter bone microarchitecture or material properties quality in young-adult and aged female C57BL/6 mice

Devine,

Brown,

Paton

et al. 2024

JBMR Plus

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Advancing age is the strongest risk factor for osteoporosis and skeletal fragility. Rapamycin is an FDA approved immunosuppressant that inhibits the mechanistic target of rapamycin (mTOR) complex, extends lifespan, and protects against aging-related diseases in multiple species; however, the impact of rapamycin on skeletal tissue is incompletely understood. We evaluated the effects of a short-term, low-dosage, interval rapamycin treatment on bone microarchitecture and strength in young-adult (3-months-old) and aged female (20-months-old) C57BL/6 mice. Rapamycin (2 mg/kg body mass) was administered via intraperitoneal injection 1x/5 days for a duration of 8 weeks; this treatment regimen has been shown to induce geroprotective effects while minimizing the side-effects associated with higher rapamycin dosages and/or more frequent or prolonged delivery schedules. Aged femurs exhibited lower cancellous bone mineral density, volume, trabecular connectivity density and number, higher trabecular thickness and spacing, and lower cortical thickness compared to young-adult mice. Rapamycin had no impact on assessed microCT parameters. Flexural testing of the femur revealed yield strength and ultimate strength were lower in aged mice compared to young-adult mice. There were no effects of rapamycin on these or other measures of bone biomechanics. Age, but not rapamycin, altered local and global measures of bone turnover. These data demonstrate a short-term, low-dosage, interval, rapamycin treatment does not negatively or positively impact the skeleton of young-adult and aged mice.

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Section: Introductionsupporting

confidence: 91%

Section: Discussioncontrasting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

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Rapamycin does not alter bone microarchitecture or material properties quality in young-adult and aged female C57BL/6 mice

Devine,

Brown,

Paton

et al. 2024

JBMR Plus

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“…With an interest in bone healing applications, the literature has conflicting findings on rapamycin’s effect on osteogenesis and osteoblast function [ 53 – 58 ]. Given that rapamycin resulted in a stark slowing of cellular metabolic processes, it is unlikely that rapamycin treated PMSCs themselves will more rapidly differentiate and contribute to the bone healing effect, as we found in our preliminary experiments (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

Rapamycin Inhibits Senescence and Improves Immunomodulatory Function of Mesenchymal Stem Cells Through IL-8 and TGF-β Signaling

Sheppard,

Delgado,

Barfield

et al. 2024

Stem Cell Rev and Rep

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Mesenchymal stromal cells (MSCs) grown in high-density monolayers (sheets) are promising vehicles for numerous bioengineering applications. When MSC sheets are maintained in prolonged cultures, they undergo rapid senescence, limiting their downstream efficacy. Although rapamycin is a potential agent that can inhibit senescence in cell cultures, no study has investigated rapamycin’s effect on MSCs grown in high-density culture and its effect on downstream target gene expression. In this study, placental-derived MSCs (PMSCs) were seeded at high density to generate PMSC sheets in 24 hours and were then treated with rapamycin or vehicle for up to 7 days. Autophagy activity, cell senescence and apoptosis, cell size and granularity, and senescence-associated cytokines (IL-6 and IL-8) were analyzed. Differential response in gene expression were assessed via microarray analysis. Rapamycin significantly increased PMSC sheet autophagy activity, inhibited cellular senescence, decreased cell size and granularity at all timepoints. Rapamycin also significantly decreased the number of cells in late apoptosis at day 7 of sheet culture, as well as caspase 3/7 activity at all timepoints. Notably, while rapamycin decreased IL-6 secretion, increased IL-8 levels were observed at all timepoints. Microarray analysis further confirmed the upregulation of IL-8 transcription, as well as provided a list of 396 genes with 2-fold differential expression, where transforming growth factor-β (TGF-β) signaling were identified as important upregulated pathways. Rapamycin both decreased senescence and has an immunomodulatory action of PMSCs grown in sheet culture, which will likely improve the chemotaxis of pro-healing cells to sites of tissue repair in future bioengineering applications. Graphical bstract

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“…Eighteen female 6-month-old C57BL/6J mice were divided into 3 groups. One week after surgery, Acacetin-EMCH-D6 (17.5 μmol/kg) and rapamycin (1 mg/kg) [ 38 ] were intraperitoneally injected every 3 d over 5 weeks.…”

Section: Methodsmentioning

confidence: 99%

An Acid-Sensitive Bone Targeting Delivery System Carrying Acacetin Prevents Osteoporosis in Ovariectomized Mice

et al. 2022

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One effective treatment for postmenopausal osteoporosis is to inhibit osteoclasts and subsequent bone resorption. In our study, we demonstrated that acacetin, a flavone with potential therapeutic effects in infections, cancers, and several metabolic disorders, inhibited osteoclast differentiation and bone resorption in vitro. For improving the efficacy of acacetin in vivo, we developed an acid-sensitive bone-targeting delivery system composed of an acid-sensitive linker (N-ε-maleimidocaproic acid hydrazide, EMCH) for ensuring an effective release of acacetin at the site of action and a hydrophilic aspartic acid hexapeptide ((Asp)6, D6) as the effective bone targeting agent. Our results revealed that Acacetin-EMCH-D6 specifically bound to the bone surface once administrated in vivo, prolonged the retention time in bone and released acacetin at the osteoclastic bone resorption sites where the acidity is higher. We further demonstrated that, in ovariectomy-induced osteoporosis mice, treatment with Acacetin-EMCH-D6 inhibited osteoclast formation and increased trabecular bone mass. On the contrary, neither acacetin nor EMCH-D6 with the same dosage alone showed significant anti-osteoporosis effects in vivo. Mechanistically, targeted delivery of acacetin to the bone resorption sites by Acacetin-EMCH-D6 inhibited autophagy through activating PI3K/AKT/mTOR pathway in osteoclasts, while the activation of autophagy by rapamycin partially reversed the inhibitory effects of acacetin in vitro and in vivo. In summary, our study, for the first time, showed that the acid-sensitive bone-targeting delivery system carrying acacetin was effective for the treatment of postmenopausal osteoporosis. Thus, targeted delivery of acacetin using Acacetin-EMCH-D6 to bone resorption sites is a promising therapy for osteoporosis.

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Rapamycin impairs bone accrual in young adult mice independent of Nrf2

Cited by 7 publications

References 52 publications

Rapamycin does not alter bone microarchitecture or material properties quality in young-adult and aged female C57BL/6 mice

Rapamycin does not alter bone microarchitecture or material properties quality in young-adult and aged female C57BL/6 mice

Rapamycin Inhibits Senescence and Improves Immunomodulatory Function of Mesenchymal Stem Cells Through IL-8 and TGF-β Signaling

An Acid-Sensitive Bone Targeting Delivery System Carrying Acacetin Prevents Osteoporosis in Ovariectomized Mice

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