Different Roles for Colony Stimulating Factor 1 Isoforms in Anabolic Therapy for Low Bone Mass

集落刺激因子 1 同工型在低骨量合成代谢治疗中的不同作用

基本信息

  • 批准号:
    10585240
  • 负责人:
  • 金额:
    $ 65.93万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-07-10 至 2028-06-30
  • 项目状态:
    未结题

项目摘要

CSF1 is the principal colony stimulating activity released by osteoblasts in response to PTH treatment. Its receptor, c-fms, is more highly expressed on mature osteoclasts than any other cell in bone. We found that deleting c-fms in osteoclasts attenuates the anabolic response to PTH. This indicates that part of PTH's anabolic actions could be via a paracrine loop in which PTH stimulates expression of CSF1 in osteoblasts, which then acts on osteoclasts to induce anabolic clastokines that augment bone formation. There are two major isoforms of CSF1: soluble (sCSF1) and membrane-associated (mCSF1). We found that the anabolic response to PTH is augmented in animals only expressing the sCSF1 isoform due to a greater increase in osteoblast number in these mice compared to PTH-treated controls. In striking contrast, animals only expressing mCSF1 had no increase in bone mass in response to an anabolic PTH regimen. Importantly, sCSF1 and mCSF1 differ in the kinetics and extent to which they activate the CSF1 receptor, c-fms, suggesting that their divergent in vivo actions may be due in part, to intrinsic differences in cell-signaling. Based on these data, we hypothesize that mCSF1 inhibits PTH anabolism by opposing the actions of sCSF1 on osteoclasts. When unopposed, sCSF1 contributes to PTH anabolism by inducing production of anabolic clastokines. Specifically, single daily doses of PTH induce transient increases in sCSF1 in osteoblasts that cause bursts of anabolic clastokine production. Consistent with this, we found that sCSF1 stimulates production of the anabolic clastokine, sphingosine-1-phosphate (S-1-P) in osteoclasts. To test these hypotheses, we will, in SA1, determine if adding intermittent dosing of sCSF1 to an anabolic PTH treatment regimen augments the skeletal response to PTH in wild type animals, while adding mCSF1 to that regimen attenuates the response. We will then try to restore the anabolic response to PTH in the sCSF1-/- mice by treating with PTH plus sCSF1. These experiments will provide pharmacologic evidence that the very different response to PTH in sCSF1-/- and mCSF1-/- mice is directly due to differing actions of the two CSF1 isoforms in bone. In SA 2, we will treat wild type mice that were ovariectomized 5 months earlier, with PTH plus sCSF1 to determine if it restores bone mass to pre-OVX levels as a model of therapy for established post-menopausal osteoporosis. In SA 3, we will determine if sCSF1 and mCSF1 induce production of different clastokine profiles in mature osteoclasts. We will use osteoblast/osteoclast cocultures as a model of in vivo paracrine signaling in bone and profile the transcriptome of osteoclasts exposed to PTH-treated osteoblasts expressing only sCSF1 or only mCSF1 to identify differences in the types of clastokines produced. We will also determine differences in the transcriptomes of osteoblasts in the cocultures stimulated by these different clastokine profiles. Finally, we will examine binding kinetics of sCSF1 and mCSF1 to c-fms, and differences in downstream signaling, to gain molecular insight into the divergent in vivo and in vitro actions of these two isoforms.
CSF1是成骨细胞对甲状旁腺激素治疗反应中释放的主要集落刺激活性。它的

项目成果

期刊论文数量(0)
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KARL Leonard INSOGNA其他文献

KARL Leonard INSOGNA的其他文献

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{{ truncateString('KARL Leonard INSOGNA', 18)}}的其他基金

An ounce of prevention: stopping menopausal bone loss before it starts
一盎司的预防:在更年期骨质流失开始之前阻止它
  • 批准号:
    10324591
  • 财政年份:
    2021
  • 资助金额:
    $ 65.93万
  • 项目类别:
The Role of Sphingosine Kinases in Bone Anabolism
鞘氨醇激酶在骨合成代谢中的作用
  • 批准号:
    9274156
  • 财政年份:
    2016
  • 资助金额:
    $ 65.93万
  • 项目类别:
A novel SATB2 mutation illuminates bone anabolism
一种新的 SATB2 突变阐明了骨合成代谢
  • 批准号:
    8874913
  • 财政年份:
    2014
  • 资助金额:
    $ 65.93万
  • 项目类别:
A novel SATB2 mutation illuminates bone anabolism
一种新的 SATB2 突变阐明了骨合成代谢
  • 批准号:
    8758799
  • 财政年份:
    2014
  • 资助金额:
    $ 65.93万
  • 项目类别:
Calcitonin for Treating X-linked Hypophosphatemia
降钙素治疗 X 连锁低磷血症
  • 批准号:
    8319251
  • 财政年份:
    2011
  • 资助金额:
    $ 65.93万
  • 项目类别:
Calcitonin for treating X-linked hypophosphatemia
降钙素治疗 X 连锁低磷血症
  • 批准号:
    8193343
  • 财政年份:
    2011
  • 资助金额:
    $ 65.93万
  • 项目类别:
Conditional Deletion of PTHrP in Articular Chondrocytes
关节软骨细胞中 PTHrP 的条件性缺失
  • 批准号:
    7609121
  • 财政年份:
    2008
  • 资助金额:
    $ 65.93万
  • 项目类别:
Conditional Deletion of PTHrP in Articular Chondrocytes
关节软骨细胞中 PTHrP 的条件性缺失
  • 批准号:
    7509044
  • 财政年份:
    2007
  • 资助金额:
    $ 65.93万
  • 项目类别:
Microcomputed tomography device (Scanco microCT35)
微型计算机断层扫描设备(Scanco microCT35)
  • 批准号:
    7389328
  • 财政年份:
    2007
  • 资助金额:
    $ 65.93万
  • 项目类别:
IMPACT OF A PROTEIN SUPPLEMENT ON BONE MASS IN OLDER WOMEN
蛋白质补充剂对老年女性骨量的影响
  • 批准号:
    7194429
  • 财政年份:
    2006
  • 资助金额:
    $ 65.93万
  • 项目类别:

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Investigating mechanisms underpinning outcomes in people on opioid agonist treatment for OUD: Disentangling sleep and circadian rhythm influences on craving and emotion regulation
研究阿片类激动剂治疗 OUD 患者结果的机制:解开睡眠和昼夜节律对渴望和情绪调节的影响
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A novel nanobody-based agonist-redirected checkpoint (ARC) molecule, aPD1-Fc-OX40L, for cancer immunotherapy
一种基于纳米抗体的新型激动剂重定向检查点 (ARC) 分子 aPD1-Fc-OX40L,用于癌症免疫治疗
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    10534864
  • 财政年份:
    2023
  • 资助金额:
    $ 65.93万
  • 项目类别:
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