Pleiotropic effects of Erythropoietin. Influence of Erythropoietin on processes of mesenchymal stem cells differentiation

Mills

Stem Cells Translational Medicine

2021

Bone homeostasis and hematopoiesis are irrevocably linked in the hypoxic environment of the bone marrow. Erythropoietin (Epo) regulates erythropoiesis by binding to its receptor, Epor, on erythroid progenitor cells. The continuous process of bone remodeling is achieved by the finely balanced activity of osteoblasts in bone synthesis and osteoclasts in bone resorption. Both osteoblasts and osteoclasts express functional Epors, but the underlying mechanism of Epo-Epor signaling in bone homeostasis is incompletely understood. Two recent publications have provided new insights into the contribution of endogenous Epo to bone homeostasis. Suresh et al examined Epo-Epor signaling in osteoblasts in bone formation in mice and Deshet-Unger et al investigated osteoclastogenesis arising from transdifferentiation of B cells. Both groups also studied bone loss in mice caused by exogenous human recombinant EPO-stimulated erythropoiesis. They found that either deletion of Epor in osteoblasts or conditional knockdown of Epor in B cells attenuates EPO-driven bone loss. These findings have direct clinical implications because patients on long-term treatment for anemia may have an increased risk of bone fractures. Phase 3 trials of small molecule inhibitors of the PHD enzymes (hypoxia inducible factor-prolyl hydroxylase inhibitors [HIF-PHIs]), such as Roxadustat, have shown improved iron metabolism and increased circulating Epo levels in a titratable manner, avoiding the supraphysiologic increases that often accompany intravenous EPO therapy. The new evidence presented by Suresh and Deshet-Unger and their colleagues on the effects of EPO-stimulated erythropoiesis on bone homeostasis seems likely to stimulate discussion on the relative merits and safety of EPO and HIF-PHIs. | INTRODUCTIONBone homeostasis is a highly organized process that requires the activity of multiple cells to coordinate bone formation and resorption.Osteoblasts, derived from mesenchymal stem cells, are responsible for bone matrix synthesis and mineralization, whereas osteoclasts derived from myeloid progenitor cells, are responsible for bone resorption. This continuous remodeling is finely balanced and is maintained by the combined action of growth factors and cytokines in the hypoxic bone marrow environment, and systemic factors such as calcitonin and estrogens. 1,2 During embryogenesis blood precursors migrate and colonize spaces created in the primitive bone marrow. 3 This close physical association provides the basis for the coordination between bone homeostasis and erythropoiesis in the bone marrow cavity that is maintained throughout adult life. The bone marrow produces

Section: The Role Of Endogenous Epo In Bone Homeostasismentioning

confidence: 99%

Section: The Role Of Endogenous Epo In Bone Homeostasismentioning

confidence: 99%

Erythropoietin in bone homeostasis—Implications for efficacious anemia therapy

Mills

Stem Cells Translational Medicine

2021

“…However, the data obtained in clinical studies did not correspond to the dynamics reflected in animal studies (Elliott et al 2017). The possible reasons for the low efficiency of erythropoietin in humans are its low affinity for the heterodimeric erythropoietin receptor, which implements cytoprotective effects, as well as the occurrence of side effects (primarily, thrombosis) due to the use of high doses (Brines and Cerami 2008, Kebschull et al 2017, Zubareva et al 2019, Agarwal 2018. In this regard, an opportunity to study a new erythropoietin derivative with a high affinity for heterodimeric erythropoietin receptors and without erythropoietic properties looked promising.…”

Section: Role Of Nuclear Factor Kappa B In the Realization Of The Renoprotective Effects Of Carbamylated Darbepoetin And Udenafil In Expementioning

confidence: 99%

“…Renoprotective properties of erythropoietin were confirmed not only in experimental, but also in clinical studies: for example, its preliminary administration in patients before performing coronary artery bypass graft surgery led to a decrease in the severity of acute kidney injury (Moore et al 2011, Tasanarong et al 2013). However, there are a number of factors that limit the use of erythropoietin as a cytoprotective agent: firstly, erythropoietin has a high affinity for classical homodimeric erythropoietin receptors and a significantly lower affinity for EPOR/ βCR (Brines and Cerami 2008, Kebschull et al 2017, Zubareva et al 2019, responsible for the cytoprotective effects. Secondly, the use of high doses of erythropoietin entails an increased risk of side effects, such as impaired hemostasis with an increased risk of thrombus formation and arterial hypertension (Agarwal 2018, Zubareva et al 2019, which also adversely affects the erythropoietin efficacy as a preconditioning agent.…”

Section: Introductionmentioning

confidence: 99%

Renoprotective effect of carbamylated darbepoetin and udenafil in ischemia-reperfusion of rat kidney due to the effect of preconditioning and inhibition of nuclear factor kappa B

Kostina¹,

Pokrovskaya²,

Poltev³

2021

RRP

Introduction: Acute kidney injury is a widespread complication in hospitalized patients, with a high mortality rate and long-term complications affecting prognosis and quality of life and with high human and financial costs. In addition, to date, no clear algorithm for the prevention of this type of damage has been developed. Materials and methods: The research was carried out on male Wistar rats. A 40-minute renal ischemia-reperfusion model was used to model acute kidney injury. Further, the renoprotective properties of carbamylated darbepoetin, udenafil and their combination were assessed based on the analysis of the biochemical studies’ results, dynamics of the renal status and the renal microvasculature, and the pathomorphological picture. A series of experiments was also carried out to assess the contribution of adenosine triphosphate-dependent potassium channels and nuclear factor kappa B to the renoprotective properties of the said agents. Results and discussion: Prophylactic administration of carbamylated darbepoetin at a dose of 50 µg/kg and udenafil at a dose of 8.7 mg/kg led to a statistically significant decrease in creatinine and blood urea nitrogen, an increase in glomerular filtration rate with a simultaneous decrease in fractional excretion of sodium, as well as an increase in the level of microcirculation in the kidneys and a decrease in the severity of damage according to the data of a pathomorphological examination at all time points of the experiment. A higher efficiency of correcting ischemic and reperfusion renal injuries was observed when using a combination of the said pharmacological agents. A series of experiments with glibenclamide demonstrated that its preliminary administration levels the renoprotective properties of carbamylated darbepoetin and udenafil. The ability of the studied pharmacological agents to reduce lipopolysaccharide-induced expression of nuclear factor kappa B in mononuclear cells was also demonstrated. The results of the research suggest that the renoprotective effects of carbamylated darbepoetin, udenafil, and their combination are realized through ATP-dependent potassium channels and nuclear factor kappa B. Conclusion: Pharmacological preconditioning with carbamylated darbepoetin and udenafil reduces the severity of acute kidney injury induced by ischemia-reperfusion. Graphical abstract:

“…Currently, EPO overall safety in patients is established by current approval for Erythropoitin and biosimilars by the US Food and Drug Administration for the treatment of anemia caused by chronic kidney disease, chemotherapy, or use of zidovudine in patients with HIV infection. Even though there have been previous reports on the effect of EPO on bone healing [ 19 ], the mechanisms which are involved in the process of bone tissue restoration via erythropoietin are still poorly understood [ 20 ] and the applicability of EPO for scaffold-guided alveolar ridge augmentation is not known. The aim of the present study was to evaluate the efficacy of erythropoietin’s angiogenic and osteogenic potential compared to two popular ridge preservation techniques anorganic bovine bone mineral (Bio-Oss ® ) with non-cross linked collagen membrane (Bio-Gide ® ), and collagen membrane alone using a rat first molar extraction model [ 18 ], and to identify the extracellular matrix-related mechanisms by which EPO affects bone regeneration.…”

Section: Introductionmentioning

confidence: 99%

The Glycoprotein/Cytokine Erythropoietin Promotes Rapid Alveolar Ridge Regeneration In Vivo by Promoting New Bone Extracellular Matrix Deposition in Conjunction with Coupled Angiogenesis/Osteogenesis

Pandya

Saxon

Bozanich

et al. 2021

IJMS

The loss of bone following tooth extraction poses a significant clinical problem for maxillofacial esthetics, function, and future implant placement. In the present study, the efficacy of an erythropoietin-impregnated collagen scaffold as an alveolar ridge augmentation material versus a conventional collagen scaffold and a BioOss inorganic bovine bone xenograft was examined. The collagen/Erythropoietin (EPO) scaffold exhibited significantly more rapid and complete osseous regeneration of the alveolar defect when compared to bone xenograft and the collagen membrane alone. The new EPO induced extracellular matrix was rich in Collagen I, Collagen III, Fibronectin (Fn) and E-cadherin, and featured significantly increased levels of the osteogenic transcription factors Runt-related transcription factor 2 (Runx2) and Osterix (Osx). Histomorphometric evaluation revealed a significant two-fold increase in the number of capillaries between the EPO and the BioOss group. Moreover, there was a highly significant 3.5-fold higher level of vascular endothelial growth factor (VEGF) in the collagen/EPO-treated group compared to controls. The significant effect of EPO on VEGF, FN, and RUNX2 upregulation was confirmed in vitro, and VEGF pathway analysis using VEGF inhibitors confirmed that EPO modulated extracellular matrix protein expression through VEGF even in the absence of blood vessels. Together, these data demonstrate the effectiveness of an EPO-impregnated collagen scaffold for bone regeneration as it induces rapid matrix production and osseoinduction adjacent to new capillaries via VEGF.