Centre for Bone and Arthritis Research, Department of Rheumatology and Inflammation Research, The Sahlgrenska Academy, University of Gothenburg Sweden.
Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, The Sahlgrenska Academy, University of Gothenburg Sweden.
Immun Inflamm Dis. 2014 Dec;2(4):214-25. doi: 10.1002/iid3.37. Epub 2014 Dec 2.
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.
第三代选择性雌激素受体调节剂 lasofoxifene（las）和 bazedoxifene（bza）被批准用于治疗绝经后骨质疏松症。17β-雌二醇（E2）和第二代 SERM 雷洛昔芬（ral）对免疫系统有重要影响，特别是对 B 细胞。E2 或 ral 的治疗抑制 B 淋巴生成，而 E2 但不是 ral 的治疗刺激抗体产生。las 和 bza 对免疫系统的影响尚未研究。因此，本研究旨在探讨它们在 B 细胞发育、成熟和功能中的作用。C57BL/6 小鼠接受假手术或卵巢切除术（ovx），并用载体、E2、ral、las 或 bza 治疗。所有物质均通过外周定量计算机断层扫描增加 ovx 小鼠的总骨矿物质密度。在子宫中，bza 单独在 ovx 小鼠中缺乏激动作用，甚至在 sham 小鼠中表现为拮抗剂。正如预期的那样，E2 减少了所有发育阶段的 B 细胞数量，从前 B I 细胞（骨髓）到过渡 1（T1）B 细胞（脾脏），并通过流式细胞术增加边缘区（MZ）B 细胞。然而，las 或 bza 的治疗仅减少骨髓 B 细胞发育和脾脏 T1 B 细胞的最后阶段，而对 MZ B 细胞没有影响。E2 增加了通过 ELISPOT 定量的产生抗体的细胞，但 las 或 bza 没有。总之，las 和 bza 通过在 B 淋巴生成和成熟过程中保留大多数 B 细胞阶段的正常细胞数量，并且不增加产生抗体的细胞，与 E2 不同。
