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Myelofibrosis: vitamin D does not help the marrow at all

There are three types of blood cell: white blood cells, red blood cells  and platelets. All three types are created from hematopoietic stem cells located in the bone marrow. Myelofibrosis causes an abnormal increase in the cells that produce collagen fibers called fibroblasts. The bone marrow becomes filled with these fibers, preventing the body from producing blood cells as normal. This condition can make it hard to control other diseases, and bone hardening (osteosclerosis) also occurs. Myelofibrosis occurs in blood tumors called myeloproliferative neoplasms, which are caused by genetic mutations of hematopoietic stem cells. Most of the times, it depends on mutation of a protein kinase involved in cell proliferation (JAK2V617F). Now, a japanese research team reveals that bone marrow disease myelofibrosis is stimulated by excessive signaling from vitamin D and immune cells known as macrophages. These findings could help to develop alternative treatments that do not target problem genes. The team was led by Research Fellow Kanako Wakahashi and Junior Associate Professor Yoshio Katayama from Kobe University Graduate School of Medicine. The research team focused on the relationship between blood-forming bone marrow and bone.

Vitamin D is a prohormone with a key role in the maintenance of both skeletal and, as is increasingly recognized, organs health. Vitamin D3 (cholecalciferol) can be obtained in the diet from animal sources or supplementation, or be produced in the skin via exposure to ultraviolet B radiation from sunlight. Vitamin D2 (ergocalciferol) is plant derived and is obtained through the diet or supplementation. For practical purposes, both forms of vitamin D can be considered bioequivalent and undergo the same metabolism, initially to 25‐hydroxyvitamin D [25(OH)D] in the liver and subsequently to 1,25‐dihydroxy D [1,25(OH)2D] in the kidney. 1,25(OH)2D is the only biologically active form of the vitamin. Dr. Katayama’s team had already shown that vitamin D receptors control the location of hematopoietic cells in the bone marrow. In this study, the team performed a bone marrow (with vitamin D receptors) transplant for a mouse model without vitamin D receptors (this means it has a high concentration of vitamin D in the body) to create a myelofibrosis model. By analyzing this model, they found that hematopoietic stem cells were strongly stimulated by vitamin D signaling and grew into immune system cells called macrophages.

These pathological macrophages stimulated young osteoblasts (cells that create bone) to induce myelofibrosis and bone hardening. The cells known as fibroblasts are thought to be these young osteoblasts. By giving these mice a low vitamin D diet and suppressing the macrophages, the team was able to largely prevent the onset of myelofibrosis. The team also examined mouse models with the same genetic disorder as myelofibrosis patients (JAK2V617F transgenic mice). These mice presented similar symptoms to myelofibrosis patients, displaying both fibrosis and bone hardening. They treated the mice by rearing them on a low vitamin D diet, blocking vitamin D receptor signals (removing the vitamin D receptor gene in blood cells) and suppressing macrophages. This proved to be extremely effective in preventing bone marrow fibrosis. The results show that pathological macrophages produced by vitamin D receptor signaling play an important role in the development of myelofibrosis. Clinical treatment uses inhibitors to target the causative genes of myeloproliferative tumors, but this is not always effective in treating myelofibrosis.

Early studies have suggested an inhibitory effect of 1,25(OH)2D on megakaryocyte proliferation and collagen synthesis in the bone marrow. It was hypothesized that 1,25(OH)2D activity contributes to a reduction in bone marrow collagen content and conversely, its deficiency allows for abnormal accumulation of collagen in the marrow. This has led to trials of vitamin D analogues for the treatment of myelofibrosis, with modest if any effect; for instance, in two small studies, treatment of primary myelofibrosis with 1‐α(OH)D3 (Alfacalcidol) failed to improve any of the disease parameters. Other studies with 1,25(OH)2D have similarly demonstrated lack of therapeutic efficacy in PMF patients. Treatment of leukemic cell lines with physiologic concentrations of 1,25(OH)2D induces their differentiation into monocytes; an initial proliferation is followed by growth arrest and terminal differentiation. A common problem is that the dose of 1,25(OH)2D that can be administered is limited by development of hypercalcemia. Consequently, efforts have focused on synthetic analogues (“deltanoids”) that have decreased calcemic activity with increased antiproliferative activity.

Examples include Doxercalciferol and Paricalcitol. Unfortunately, these newer compounds also appear to have minimal therapeutic activity in myelodysplastic syndromes. What the team discovered may explain the reason and the failure of the clinical outcomes. Professor Katayama commente: “The only permanent cure for this disease is hematopoietic stem cell transplant, but this method is unsuitable for many elderly patients. These new findings may help to develop a treatment method for the elderly targeting the vitamin D pathway and macrophages”.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry

Scientific references

Wakahashi K et al., Katayama Y. Blood. 2019 Feb 4.

Medrano M et al. Int J Mol Sci. 2018 Sep 8; 19(9).

Song IG, Park CJ. Blood Res. 2014 Jun;49(2):84.

Pardanani A et al. Am J Hematol. 2011; 86(12):1013.

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Dott. Gianfrancesco Cormaci
Dott. Gianfrancesco Cormaci
Laurea in Medicina e Chirurgia nel 1998, specialista in Biochimica Clinica dal 2002, ha conseguito dottorato in Neurobiologia nel 2006. Ex-ricercatore, ha trascorso 5 anni negli USA alle dipendenze dell' NIH/NIDA e poi della Johns Hopkins University. Guardia medica presso la casa di Cura Sant'Agata a Catania. In libera professione, si occupa di Medicina Preventiva personalizzata e intolleranze alimentari. Detentore di un brevetto per la fabbricazione di sfarinati gluten-free a partire da regolare farina di grano. Responsabile della sezione R&D della CoFood s.r.l. per la ricerca e sviluppo di nuovi prodotti alimentari, inclusi quelli a fini medici speciali.

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