Abstract：
X-linked hypophosphatemia (XLH) is caused by mutations in PHEX, leading to rickets and osteomalacia. Adults affected with XLH develop a mineralization of the bone-tendon attachment site (enthesis), called enthesopathy, which causes significant pain and impaired movement. Entheses in mice with XLH (Hyp) have enhanced Bone Morphogenetic Protein (BMP) and Indian hedgehog (IHH) signaling. Treatment of Hyp mice with the BMP signaling blocker palovarotene attenuated BMP/IHH signaling in Hyp entheses, thus indicating that BMP signaling plays a pathogenic role in enthesopathy development and that IHH signaling is activated by BMP signaling in entheses. It was previously shown that mRNA expression of Gdf5 is enhanced in Hyp entheses at P14. Thus, to determine a role for GDF5 in enthesopathy development, Gdf5 was deleted globally in Hyp mice and conditionally in Scx + cells of Hyp mice. In both murine models, BMP/IHH signaling was similarly decreased in Hyp entheses, leading to decreased enthesopathy. BMP/IHH signaling remained unaffected in WT entheses with decreased Gdf5 expression. Moreover, deletion of Gdf5 in Hyp entheses starting at P30, after enthesopathy has developed, partially reversed enthesopathy. Taken together, these results demonstrate that while GDF5 is not essential for modulating BMP/IHH signaling in WT entheses, inappropriate GDF5 activity in Scx + cells contributes to XLH enthesopathy development. As such, inhibition of GDF5 signaling may be beneficial for the treatment of XLH enthesopathy.
X-linked hypophosphatemia (XLH) is a rare bone disorder that leads to short stature and poorly mineralized bones. As adults, patients with XLH often develop a mineralization of the bone-tendon attachment site, called enthesopathy, that results in significant pain. We previously showed that Achilles bone-tendon attachment sites (entheses) in mice with XLH (Hyp) have an enthesopathy characterized by increased Bone Morphogenetic Protein (BMP) signaling. In the current studies, we show that treating Hyp mice with the BMP signaling inhibitor palovarotene prevents enthesopathy, demonstrating that the increased BMP signaling in Hyp entheses leads to enthesopathy development. We also reported that expression of Gdf5, which activates BMP signaling, is enhanced in Hyp entheses. Therefore, to determine if the enhanced Gdf5 expression leads to the increased BMP signaling seen Hyp entheses, Gdf5 was deleted from Hyp mice and also deleted specifically in the entheses of Hyp mice. In both mouse models, enthesopathy development was attenuated, demonstrating that the increased Gdf5 expression in Hyp entheses plays a role in enthesopathy development. These data indicate that blocking GDF5 and BMP signaling may prevent enthesopathy in patients with XLH.
X-linked hypophosphatemia (XLH) is a rare bone disorder that leads to short stature and poorly mineralized bones. As adults, patients with XLH often develop a mineralization of the bone-tendon attachment site, called enthesopathy, that results in significant pain. We previously showed that Achilles bone-tendon attachment sites (entheses) in mice with XLH (Hyp) have an enthesopathy characterized by increased Bone Morphogenetic Protein (BMP) signaling. In the current studies, we show that treating Hyp mice with the BMP signaling inhibitor palovarotene prevents enthesopathy, demonstrating that the increased BMP signaling in Hyp entheses leads to enthesopathy development. We also reported that expression of Gdf5, which activates BMP signaling, is enhanced in Hyp entheses. Therefore, to determine if the enhanced Gdf5 expression leads to the increased BMP signaling seen Hyp entheses, Gdf5 was deleted from Hyp mice and also deleted specifically in the entheses of Hyp mice. In both mouse models, enthesopathy development was attenuated, demonstrating that the increased Gdf5 expression in Hyp entheses plays a role in enthesopathy development. These data indicate that blocking GDF5 and BMP signaling may prevent enthesopathy in patients with XLH.
摘要：
X连锁低磷酸盐血症（XLH）是由PHEX突变引起的，导致病和骨软化症.受XLH影响的成年人会发生骨腱附着部位的矿化（发生），叫做enthesopathy，导致严重的疼痛和运动受损。具有XLH(Hyp)的小鼠中的末端具有增强的骨形态发生蛋白(BMP)和印度刺猬(IHH)信号传导。用BMP信号阻断剂palovarotene治疗Hyp小鼠减弱了Hyp的BMP/IHH信号，因此，表明BMP信号传导在肠病的发展中起致病作用，并且IHH信号传导在实验中被BMP信号激活。先前显示，在P14的Hypenthesis中，Gdf5的mRNA表达增强。因此，为了确定GDF5在末端病变发展中的作用，在Hyp小鼠中和在Hyp小鼠的Scx+细胞中条件性地缺失Gdf5。在两种鼠类模型中，BMP/IHH信号在Hyp实验中同样降低，导致耳部病变减少。BMP/IHH信号传导在Gdf5表达降低的WT中保持不受影响。此外，在P30开始的Hypenthesis中Gdf5的缺失，在enthespathy发展后，部分逆转的附着物病。一起来看,这些结果表明，虽然GDF5对于在WT中调节BMP/IHH信号传导不是必需的，Scx+细胞中不适当的GDF5活性有助于XLH末端病变的发展。因此，抑制GDF5信号传导可能对治疗XLH末端病变有益.
X连锁低磷酸盐血症（XLH）是一种罕见的骨骼疾病，可导致身材矮小和骨骼矿化不良。作为成年人,XLH患者通常会发生骨-肌腱附着部位的矿化，叫做enthesopathy，导致严重的疼痛。我们先前表明，XLH（Hyp）小鼠的跟腱骨附着位点（enthes）具有以骨形态发生蛋白（BMP）信号增加为特征的附着点病。在目前的研究中,我们表明，用BMP信号抑制剂帕罗瓦汀治疗Hyp小鼠可以预防附着点病，证明Hypentheses中BMP信号的增加导致了末端病变的发展。我们还报道了激活BMP信号的Gdf5的表达，在Hyp实例中得到了增强。因此,为了确定增强的Gdf5表达是否导致观察到Hypenthesis的BMP信号增加，从Hyp小鼠中删除了Gdf5，并且在Hyp小鼠的小鼠中也特别删除了Gdf5。在两种小鼠模型中，enthesopathy发展减弱，证明Hypentheses中Gdf5表达的增加在enthesis病的发展中起作用。这些数据表明阻断GDF5和BMP信号传导可以预防XLH患者的末端病变。
X连锁低磷酸盐血症（XLH）是一种罕见的骨骼疾病，可导致身材矮小和骨骼矿化不良。作为成年人,XLH患者通常会发生骨-肌腱附着部位的矿化，叫做enthesopathy，导致严重的疼痛。我们先前表明，XLH（Hyp）小鼠的跟腱骨附着位点（enthes）具有以骨形态发生蛋白（BMP）信号增加为特征的附着点病。在目前的研究中,我们表明，用BMP信号抑制剂帕罗瓦汀治疗Hyp小鼠可以预防附着点病，证明Hypentheses中BMP信号的增加导致了末端病变的发展。我们还报道了激活BMP信号的Gdf5的表达，在Hyp实例中得到了增强。因此,为了确定增强的Gdf5表达是否导致观察到Hypenthesis的BMP信号增加，从Hyp小鼠中删除了Gdf5，并且在Hyp小鼠的小鼠中也特别删除了Gdf5。在两种小鼠模型中，enthesopathy发展减弱，证明Hypentheses中Gdf5表达的增加在enthesis病的发展中起作用。这些数据表明阻断GDF5和BMP信号传导可以预防XLH患者的末端病变。
