Departments of Medicine, Yale School of Medicine, New Haven, CT, United States of America.
Departments of Immunobiology, Yale School of Medicine, New Haven, CT, United States of America.
PLoS One. 2021 Feb 19;16(2):e0247199. doi: 10.1371/journal.pone.0247199. eCollection 2021.
The receptor for Colony Stimulating Factor 1 (CSF1), c-fms, is highly expressed on mature osteoclasts suggesting a role for this cytokine in regulating the function of these cells. Consistent with this idea, in vitro studies have documented a variety of effects of CSF1 in mature osteoclasts. To better define the role of CSF1 in these cells, we conditionally deleted c-fms in osteoclasts (c-fms-OC-/-) by crossing c-fmsflox/flox mice with mice expressing Cre under the control of the cathepsin K promoter. The c-fms-OC-/- mice were of normal weight and had normal tooth eruption. However, when quantified by DXA, bone mass was significantly higher in the spine and femur of female knock out mice and in the femurs of male knock out mice. MicroCT analyses of femurs showed that female c-fms-OC-/- mice had significantly increased trabecular bone mass with a similar trend in males and both sexes demonstrated significantly increased trabecular number and reduced trabecular spacing. Histomorphometric analysis of the femoral trabecular bone compartment demonstrated a trend towards increased numbers of osteoclasts, +26% in Noc/BPm and +22% in OcS/BS in the k/o animals but this change was not significant. However, when the cellular volume of osteoclasts was quantified, the c-fms-OC-/- cells were found to be significantly smaller than controls. Mature osteoclasts show a marked spreading response when exposed to CSF1 in a non-gradient fashion. However, osteoclasts freshly isolated from c-fms-OC-/- mice had a near complete abrogation of this response. C-fms-OC-/- mice treated with (1-34)hPTH 80 ng/kg/d in single daily subcutaneous doses for 29 days showed an attenuated anabolic response in trabecular bone compared to wild-type animals. Taken together, these data indicate an important non-redundant role for c-fms in regulating mature osteoclast function in vivo.
集落刺激因子 1（CSF1）受体 c-fms 在成熟破骨细胞上高度表达，表明该细胞因子在调节这些细胞的功能中起作用。与这一观点一致，体外研究记录了 CSF1 在成熟破骨细胞中的多种作用。为了更好地定义 CSF1 在这些细胞中的作用，我们通过将 c-fmsflox/flox 小鼠与在组织蛋白酶 K 启动子控制下表达 Cre 的小鼠进行杂交，在破骨细胞中条件性删除 c-fms（c-fms-OC-/-）。c-fms-OC-/- 小鼠体重正常，牙齿正常萌出。然而，通过 DXA 定量，雌性敲除小鼠的脊柱和股骨以及雄性敲除小鼠的股骨骨量明显更高。股骨的 microCT 分析表明，雌性 c-fms-OC-/- 小鼠的小梁骨量明显增加，雄性也有类似的趋势，两性的小梁数都明显增加，小梁间距减小。股骨小梁骨腔的组织形态计量学分析表明，破骨细胞数量有增加的趋势，k/o 动物的 Noc/BPm 中增加了+26%，OcS/BS 中增加了+22%，但这种变化并不显著。然而，当量化破骨细胞的细胞体积时，发现 c-fms-OC-/- 细胞明显小于对照细胞。成熟的破骨细胞在非梯度方式下暴露于 CSF1 时表现出明显的扩散反应。然而，从 c-fms-OC-/- 小鼠中分离的破骨细胞几乎完全消除了这种反应。用 1-34）hPTH 80 ng/kg/d 每天一次皮下注射，连续 29 天，c-fms-OC-/- 小鼠的小梁骨对（1-34）hPTH 的合成反应减弱，与野生型动物相比。综上所述，这些数据表明 c-fms 在调节体内成熟破骨细胞功能方面具有重要的非冗余作用。
