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Effects of lasofoxifene and bazedoxifene on B cell development and function.

Bernardi AI, Andersson A, Grahnemo L, Nurkkala-Karlsson M, Ohlsson C, Carlsten H, Islander U - Immun Inflamm Dis (2014)

Bottom Line: However, treatment with las or bza only decreased the last stages of bone marrow B cell development and splenic T1 B cells, but had no effect MZ B cells.E2 increased antibody-producing cells quantified by ELISPOT, but las or bza did not.In conclusion, las and bza differ from E2 by retaining normal number of cells at most B cell stages during B lymphopoiesis and maturation and by not increasing antibody-producing cells.

View Article: PubMed Central - PubMed

Affiliation: Centre for Bone and Arthritis Research, Department of Rheumatology and Inflammation Research, The Sahlgrenska Academy, University of Gothenburg Sweden.

ABSTRACT
The third generation selective estrogen receptor modulators lasofoxifene (las) and bazedoxifene (bza) are indicated for treatment of postmenopausal osteoporosis. 17β-Estradiol (E2) and the second generation SERM raloxifene (ral) have major effects on the immune system, particularly on B cells. Treatment with E2 or ral inhibits B lymphopoiesis and treatment with E2, but not ral, stimulates antibody production. The effects of las and bza on the immune system have not been studied. Therefore, the aim of this study was to investigate their role in B cell development, maturation, and function. C57BL/6 mice were sham-operated or ovariectomized (ovx) and treated with vehicle, E2, ral, las, or bza. All substances increased total bone mineral density in ovx mice, as measured by peripheral quantitative computed tomography. In uterus, bza alone lacked agonistic effect in ovx mice and even acted as an antagonist in sham mice. As expected, E2 decreased B cell numbers at all developmental stages from pre-BI cells (in bone marrow) to transitional 1 (T1) B cells (in spleen) and increased marginal zone (MZ) B cells as determined by flow cytometry. However, treatment with las or bza only decreased the last stages of bone marrow B cell development and splenic T1 B cells, but had no effect MZ B cells. E2 increased antibody-producing cells quantified by ELISPOT, but las or bza did not. In conclusion, las and bza differ from E2 by retaining normal number of cells at most B cell stages during B lymphopoiesis and maturation and by not increasing antibody-producing cells.

No MeSH data available.


Related in: MedlinePlus

E2 decreases pre-BI cells in bone marrow of ovx mice. (a) Gating strategy for pro-B cells and pre-BI cells: B220lowc-kit+ cells (left) were gated and further divided into CD19− (pro-B cells) and CD19+ (pre-BI cells) (right). Number of (b) pro-B cells and (c) pre-BI cells of bone marrow lymphocytes in sham (left) or ovx (right) mice treated with vehicle, E2 or SERMs, n = 5–10 mice/group. Data expressed as mean + SEM (*P < 0.05, **P < 0.01).
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fig02: E2 decreases pre-BI cells in bone marrow of ovx mice. (a) Gating strategy for pro-B cells and pre-BI cells: B220lowc-kit+ cells (left) were gated and further divided into CD19− (pro-B cells) and CD19+ (pre-BI cells) (right). Number of (b) pro-B cells and (c) pre-BI cells of bone marrow lymphocytes in sham (left) or ovx (right) mice treated with vehicle, E2 or SERMs, n = 5–10 mice/group. Data expressed as mean + SEM (*P < 0.05, **P < 0.01).

Mentions: Estrogen has an inhibitory effect on B cell differentiation and survival at the pro-B cell stage, preventing the transition to pre-B cells 6,12. In order to investigate how SERMs affect the transition between the two earliest stages of B cell development, the pro-B and pre-BI populations were identified by analyzing the expression of B220, c-kit and CD19. Both populations express B220 and c-kit (Fig. 2a, left). In order to divide the c-kit+ population into pro-B and pre-BI cells, CD19 was used as it is not yet expressed on pro-B cells, but up-regulated on pre-BI cells (Fig. 2a, right). None of the treatments altered the number of pro-B cells in sham or ovx mice (Fig. 2b). However, E2 decreased pre-BI cells with 90% in ovx mice compared with controls, while this population remained intact in SERM-treated mice (Fig. 2c, right). In sham-operated mice no changes were observed in the number of pre-BI cells (Fig. 2c, left).


Effects of lasofoxifene and bazedoxifene on B cell development and function.

Bernardi AI, Andersson A, Grahnemo L, Nurkkala-Karlsson M, Ohlsson C, Carlsten H, Islander U - Immun Inflamm Dis (2014)

E2 decreases pre-BI cells in bone marrow of ovx mice. (a) Gating strategy for pro-B cells and pre-BI cells: B220lowc-kit+ cells (left) were gated and further divided into CD19− (pro-B cells) and CD19+ (pre-BI cells) (right). Number of (b) pro-B cells and (c) pre-BI cells of bone marrow lymphocytes in sham (left) or ovx (right) mice treated with vehicle, E2 or SERMs, n = 5–10 mice/group. Data expressed as mean + SEM (*P < 0.05, **P < 0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4386916&req=5

fig02: E2 decreases pre-BI cells in bone marrow of ovx mice. (a) Gating strategy for pro-B cells and pre-BI cells: B220lowc-kit+ cells (left) were gated and further divided into CD19− (pro-B cells) and CD19+ (pre-BI cells) (right). Number of (b) pro-B cells and (c) pre-BI cells of bone marrow lymphocytes in sham (left) or ovx (right) mice treated with vehicle, E2 or SERMs, n = 5–10 mice/group. Data expressed as mean + SEM (*P < 0.05, **P < 0.01).
Mentions: Estrogen has an inhibitory effect on B cell differentiation and survival at the pro-B cell stage, preventing the transition to pre-B cells 6,12. In order to investigate how SERMs affect the transition between the two earliest stages of B cell development, the pro-B and pre-BI populations were identified by analyzing the expression of B220, c-kit and CD19. Both populations express B220 and c-kit (Fig. 2a, left). In order to divide the c-kit+ population into pro-B and pre-BI cells, CD19 was used as it is not yet expressed on pro-B cells, but up-regulated on pre-BI cells (Fig. 2a, right). None of the treatments altered the number of pro-B cells in sham or ovx mice (Fig. 2b). However, E2 decreased pre-BI cells with 90% in ovx mice compared with controls, while this population remained intact in SERM-treated mice (Fig. 2c, right). In sham-operated mice no changes were observed in the number of pre-BI cells (Fig. 2c, left).

Bottom Line: However, treatment with las or bza only decreased the last stages of bone marrow B cell development and splenic T1 B cells, but had no effect MZ B cells.E2 increased antibody-producing cells quantified by ELISPOT, but las or bza did not.In conclusion, las and bza differ from E2 by retaining normal number of cells at most B cell stages during B lymphopoiesis and maturation and by not increasing antibody-producing cells.

View Article: PubMed Central - PubMed

Affiliation: Centre for Bone and Arthritis Research, Department of Rheumatology and Inflammation Research, The Sahlgrenska Academy, University of Gothenburg Sweden.

ABSTRACT
The third generation selective estrogen receptor modulators lasofoxifene (las) and bazedoxifene (bza) are indicated for treatment of postmenopausal osteoporosis. 17β-Estradiol (E2) and the second generation SERM raloxifene (ral) have major effects on the immune system, particularly on B cells. Treatment with E2 or ral inhibits B lymphopoiesis and treatment with E2, but not ral, stimulates antibody production. The effects of las and bza on the immune system have not been studied. Therefore, the aim of this study was to investigate their role in B cell development, maturation, and function. C57BL/6 mice were sham-operated or ovariectomized (ovx) and treated with vehicle, E2, ral, las, or bza. All substances increased total bone mineral density in ovx mice, as measured by peripheral quantitative computed tomography. In uterus, bza alone lacked agonistic effect in ovx mice and even acted as an antagonist in sham mice. As expected, E2 decreased B cell numbers at all developmental stages from pre-BI cells (in bone marrow) to transitional 1 (T1) B cells (in spleen) and increased marginal zone (MZ) B cells as determined by flow cytometry. However, treatment with las or bza only decreased the last stages of bone marrow B cell development and splenic T1 B cells, but had no effect MZ B cells. E2 increased antibody-producing cells quantified by ELISPOT, but las or bza did not. In conclusion, las and bza differ from E2 by retaining normal number of cells at most B cell stages during B lymphopoiesis and maturation and by not increasing antibody-producing cells.

No MeSH data available.


Related in: MedlinePlus