Intraperitoneal injection of Desferal® alleviated the age-related bone loss and senescence of bone marrow stromal cells in rats

Abstract

Background Age-related bone loss plays a vital role in the development of osteoporosis and osteoporotic fracture. Bone marrow stromal cell (BMSC) senescence is highly associated with osteoporosis and limits the application of BMSCs in regenerative medicine. Hypoxia is an essential component for maintaining the normal physiology of BMSCs. We have reported that activation of hypoxia-induced factor by deletion of von Hippel-Lindau gene in osteochondral progenitor cells protected mice from aging-induced bone loss. However, whether pharmacologically manipulation of hypoxic niche would attenuate age-related bone loss and dysfunction of BMSCs is not well understood. Methods Twelve-month-old Sprague-Dawley rats were used as an aged model and were intraperitoneally injected with Desferal® (20, 60 mg/kg weight or vehicle), three times a week for a continuous 8-week period. Two-month-old young rats were set as a reference. After 8 weeks, micro-CT and HE staining were performed to determine the effect of Desferal® on bone loss. In order to investigate the effects of Desferal® on BMSC senescence, 12-month-old rats were treated with high-dose Desferal® (60 mg/kg weight) daily for 10 days. BMSCs were isolated and evaluated using CCK-8 assay, colony-forming cell assay, cell differentiation assay, laser confocal for reactive oxygen species (ROS) level, senescence-associated β-galactosidase (SA-β-gal) staining, and molecular expression test for stemness/senescence-associated genes. Results Micro-CT and HE staining showed that high-dose Desferal® significantly prevented bone loss in aged rats. Compared with vehicle group, the ex vivo experiments showed that short-term Desferal® administration could promote the potential of BMSC growth (proliferation and colony formation ability) and improve the rebalance of osteogenic and adipogenic differentiation, as well as rejuvenate senescent BMSCs (ROS level and SA-β-gal staining) and revise the expression of stemness/senescence-associated genes. The potential of BMSCs from 12M-H-Desferal® group at least partly revised to the level close to 2-month-old group. Conclusions The current study suggested that Desferal®, an iron-chelating agent, could alleviate age-related bone loss in middle-aged rats. Meanwhile, we found that short-term intraperitoneal injection of Desferal® partly rejuvenate BMSCs from aged rats. Overall, we demonstrated a novel role of Desferal® in rejuvenating aged BMSCs and preventing age-related bone loss.

Ganoderic acid D prevents oxidative stress‐induced senescence by targeting 14‐3‐3ε to activate CaM/CaMKII/NRF2 signaling pathway in mesenchymal stem cells

“…However, senescent stem cells lose the ability to repair damaged tissues, impair the homeostasis in the tissue, and even cause age‐related diseases. In the organisms, increasing evidence indicates that aging may cause the senescence and reduce the number of stem cells (Cianflone et al, 2020 ; Díaz‐Morenoa et al, 2018 ; Tian & Li, 2014 ; Vilas et al, 2018 ; Vyver et al, 2021 ; Yi et al, 2021 ). For instance, hematopoietic stem cells (HSCs) are incapable of regenerating the damaged hematopoietic system as efficiently as young HSCs, which eventually leads to hematopoietic dysfunction and other related diseases (Chen & Ju, 2019 ).…”

Ferroptosis and Its Role in Chronic Diseases

“…There are two mechanisms of ferroptosis inhibitors: (1) inhibiting the accumulation of iron, such as that of deferoxamine (DFO), which chelates iron and limits the Fenton reaction to prevent lipid peroxidation; and (2) the inhibition of lipid peroxidation by, for example, ferrostatin-1 (Fer-1), liproxststatin-1 (Lip-1), and vitamin E, which act as radical scavengers to reduce lipid peroxides and effectively block ferroptosis. DFO is commercially available as Desferal, an iron chelator clinically approved for the treatment of acute iron intoxication and chronic iron overload [65]. For the action mechanism, Desferal is a hexadentate molecule that is able to bind free plasma iron and excess iron within cells at a 1-to-1 ratio and then is excreted via the urine or bile [66].…”

Regulation of bone health through physical exercise: Mechanisms and types

“…Age-related bone loss is associated with accelerated bone resorption and lower bone formation, resulting in osteoporosis and related fractures. Resembling other types of osteoporosis conditions, age-related bone loss is associated with a systemic bone loss related to trabecular and cortical compartments, osteopenia, osteoporosis, and subsequently high fracture risk ( 90 ). The number of patients who suffer from age-related bone fracture has substantially increased because of the global aging.…”

“…Physical activity is considered an effective support for improving bone health in older people ( 90 ). The number of HSCs is upregulated by physical activity or exercise ( 96 , 97 ).…”