Myeloid progenitors from the bone marrow of patients with vitamin D resistant rickets (type II) fail to respond to 1,25(OH)2D3.
The active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), has been shown to enhance the growth of human granulocyte/macrophage haemopoietic progenitors in vitro and to induce these cells to differentiate along the monocyte/macrophage pathway. In order to evaluate the relationship between specific receptors for 1,25(OH)2D3 and the role of 1,25(OH2D3 in the regulation of haemopoietic cell differentiation, we examined the effect of haemopoietic cell differentiation, we examined the effect of 1,25(OH)2D3 on the in vitro growth and differentiation patterns of marrow myeloid progenitor cells from two patients with 1,25(OH)2D3 resistant rickets, resulting from defective receptors to vitamin D. A significant rise in the frequency of myeloid colonies in control marrow cell cultures was induced by 2 X 10(-9) to 2 X 10(-7)M 1,25(OH)2D3. This rise reached a plateau at 2 X 10(-9)_2 X 10(-8) M 1,25(OH)2D3, resulting in a maximal 54 +/- 9% increase in colony numbers. In contrast, no stimulatory effect could be detected when 1,25(OH)2D3 was added to cultured marrow cells from the patients with 1,25(OH)2D3 resistance. Analysis of colony composition revealed that 2 X 10(-8) and 2 X 10(-7) M, 1,25(OH)2D3 induced a 50 +/- 26% increase in the frequency of colonies composed only of monocytes/macrophages in control, but not in the patients' marrow cell cultures. The effect of 2 X 10(-8) and 2 X 10(-7) M 1,25(OH)2D3 on progenitor cell differentiation towards monocytes/macrophages was also observed in marrow cell suspension cultures. Whereas 1,25(OH)2D3 induced a 81-136% increase in the frequency of monocytes in control marrow cells, no effect could be detected on the generation of mature monocytes in marrow cells of the 1,25(OH)2D3 resistant patients. Our results show that marrow granulocyte/macrophage progenitor cells from patients with 1,25(OH)2D3 resistance fail to respond to 1,25(OH)2D3. We thus demonstrate that the effect of 1,25(OH)2D3 on the proliferation and differentiation of haemopoietic progenitor cells is mediated through its binding to specific cytoplasmic receptors.
Nagler
A
A
Department of Hematology, Rambam Medical Center, Haifa, Israel.
Merchav
S
S
Fabian
I
I
Tatarsky
I
I
Weisman
Y
Y
Hochberg
Z
Z
D001853:Bone Marrow / Q000473:pathology*; D002117:Calcitriol / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D003114:Colony-Forming Units Assay; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D006801:Humans; D007015:Hypophosphatemia, Familial / Q000473:pathology*; D008297:Male; D009000:Monocytes / Q000473:pathology
D002117:Calcitriol