Sclerostin Depletion Induces Inflammation in the Bone Marrow of Mice.
Sclerostin Depletion Induces Inflammation in the Bone Marrow of Mice.
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DOI：
10.3390/ijms22179111
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发表时间：
2021-08-24
影响因子：
5.6
通讯作者：
Manilay JO
中科院分区：
文献类型：
--
作者：
Donham C;Chicana B;Robling AG;Mohamed A;Elizaldi S;Chi M;Freeman B;Millan A;Murugesh DK;Hum NR;Sebastian A;Loots GG;Manilay JO
Romosozumab是一种针对硬化蛋白（SOST）的人源化单克隆抗体，已被批准用于治疗绝经后骨质疏松症的骨折高风险妇女。先前在硬化蛋白全敲除（Sost - / -）小鼠中的研究表明，骨髓（BM）免疫细胞发育发生改变，这可能是romosozumab治疗患者的一个可能的副作用。在这里，我们研究了BM中短期硬化蛋白缺失对接受6周硬化蛋白抗体（Scl-Ab）治疗的年轻小鼠造血功能的影响，以及长期缺乏Sost对野生型（WT）长期造血干细胞移植到老年Sost - / -小鼠中的影响。我们的分析显示，scl - ab处理小鼠和WT→Sost - / -嵌合体的骨髓中粒细胞频率增加，表明在Sost缺乏的骨髓微环境中存在骨髓偏向分化。这种髓系偏向扩展到脾髓外造血，并与Sost - / - BM血清中炎症细胞因子tnf - α、IL-1α和MCP-1的增加相关。此外，我们观察到Sost - / -小鼠BM和脾脏红细胞分化的改变。综上所述，我们目前的研究表明Sost在调节骨髓生成和控制BM炎症中的新作用。
Romosozumab, a humanized monoclonal antibody specific for sclerostin (SOST), has been approved for treatment of postmenopausal women with osteoporosis at a high risk for fracture. Previous work in sclerostin global knockout (Sost−/−) mice indicated alterations in immune cell development in the bone marrow (BM), which could be a possible side effect in romosozumab-treated patients. Here, we examined the effects of short-term sclerostin depletion in the BM on hematopoiesis in young mice receiving sclerostin antibody (Scl-Ab) treatment for 6 weeks, and the effects of long-term Sost deficiency on wild-type (WT) long-term hematopoietic stem cells transplanted into older cohorts of Sost−/− mice. Our analyses revealed an increased frequency of granulocytes in the BM of Scl-Ab-treated mice and WT→Sost−/− chimeras, indicating myeloid-biased differentiation in Sost-deficient BM microenvironments. This myeloid bias extended to extramedullary hematopoiesis in the spleen and was correlated with an increase in inflammatory cytokines TNFα, IL-1α, and MCP-1 in Sost−/− BM serum. Additionally, we observed alterations in erythrocyte differentiation in the BM and spleen of Sost−/− mice. Taken together, our current study indicates novel roles for Sost in the regulation of myelopoiesis and control of inflammation in the BM.
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影响因子：
2.7
作者：
Collette, Nicole M.;Genetos, Damian C.;Murugesh, Deepa;Harland, Richard M.;Loots, Gabriela G.
通讯作者：
Loots, Gabriela G.
影响因子：
12.8
作者：
Gravano DM;Al-Kuhlani M;Davini D;Sanders PD;Manilay JO;Hoyer KK
通讯作者：
Hoyer KK
影响因子：
8.7
作者：
Dinarello CA
通讯作者：
Dinarello CA
影响因子：
23.9
作者：
Duarte D;Hawkins ED;Akinduro O;Ang H;De Filippo K;Kong IY;Haltalli M;Ruivo N;Straszkowski L;Vervoort SJ;McLean C;Weber TS;Khorshed R;Pirillo C;Wei A;Ramasamy SK;Kusumbe AP;Duffy K;Adams RH;Purton LE;Carlin LM;Lo Celso C
通讯作者：
Lo Celso C
影响因子：
1.5
作者：
EVANS T C;JEHLE D
通讯作者：
JEHLE D