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A Hypoxia Mimetic Drug Improves the Bone Marrow Environment to Treat Osteoarthritis

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Posted 15 January 2021 - 11:11 AM

Researchers here show that an iron chelation drug (deferoxamine, brand name desferal) triggers a portion of the cellular reaction to hypoxia in bone marrow. Hypoxia is one of the many types of stress that, when mild, induces cells to greater efforts in maintenance and repair, resulting in a net gain in cell function. In the rats treated with deferoxamine in this study, the hypoxia mimetic acts to reduce the burden of cellular senescence, and otherwise shift the behavior of cells in the direction of slowing the onset of osteoporosis.

Bone marrow stromal cells (BMSCs) exist in the bone marrow with multi-potency and have a broad application prospect in the field of cell therapy and regenerative medicine thanks to their accessibility and expansion potential. Previous study showed a high potential association between BMSC senescence and age-related bone loss. Several studies have documented that age drives the intrinsic alterations of BMSCs, including decreased proliferation and osteogenic differentiation potential, as well as increased senescence-associated gene expression and β-galactosidase-positive staining. It also reported that the viability of aged BMSCs decreased, and senescent BMSCs were more likely to differentiate into adipocytes. These changes led to the decrease in quantity and quality of BMSCs, which together contributed to age-related bone loss.

Oxygen is a fundamental element of the bone marrow niche, and a hypoxic environment in the bone marrow is generally considered to be indispensable for retaining normal physiological function and self-renewal of stromal cells. As the key transcription factor response to hypoxia stress, hypoxia-induced factor 1α (HIF-1α) is a highly unstable protein in normoxic conditions. However, under hypoxic conditions, the catalytic activity of prolyl hydroxylases (PHD) is inhibited, leading to the stabilized expression of HIF-1α. Some small molecules, such as deferoxamine (DFO), are known as hypoxia mimics, which can elevate HIF-1α levels by blocking PHD activity even in normoxic conditions.

In this study, Desferal, deferoxamine mesylate for injection, which is approved for the treatment of acute iron intoxication and chronic iron overload, was used to explore the beneficial effects on preventing aging-induced bone loss and mitigating dysfunction of aged BMSCs. High-dose Desferal significantly prevented bone loss in aged rats. Compared with controls, the ex vivo experiments showed that short-term Desferal administration could promote the potential of BMSC growth and improve the rebalance of osteogenic and adipogenic differentiation, as well as rejuvenate senescent BMSCs and revise the expression of stemness/senescence-associated genes. The potential of BMSCs from the Desferal group at least partly revised to the level close to that of the 2-month-old group.

Link: https://doi.org/10.1...287-020-02112-9

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