Palovarotene reduces heterotopic ossification in juvenile FOP mice but exhibits pronounced skeletal toxicity.
Palovarotene reduces heterotopic ossification in juvenile FOP mice but exhibits pronounced skeletal toxicity.
复制标题
DOI：
10.7554/elife.40814
复制
发表时间：
2018-09-18
期刊：
影响因子：
7.7
通讯作者：
Goldhamer DJ
中科院分区：
文献类型：
--
作者：
Lees-Shepard JB;Nicholas SE;Stoessel SJ;Devarakonda PM;Schneider MJ;Yamamoto M;Goldhamer DJ
进行性骨化性纤维发育不良（FOP）是一种罕见的遗传性疾病，其特征是使人衰弱的异位骨化（HO）。维甲酸受体γ激动剂、palovarotene和抗体介导的激活素A阻断剂已进入人体临床试验，但这些治疗方式如何影响致病性脂肪祖细胞（FAP）的行为尚不清楚。使用活体动物发光成像，我们表明，移植的致病性FAP经历快速的初始扩张，峰值数量与HO严重程度密切相关。帕罗伐汀显著降低致病性FAP的扩增，但不如激活素A抑制有效，激活素A抑制恢复了FAP的野生型群体生长动力学。帕罗伐汀预处理没有降低FAP的成骨潜力，表明疗效需要长期给药。尽管帕洛伐他汀在体外抑制软骨形成分化并减少幼年FOP小鼠的HO，但每天给药会导致侵袭性滑液关节过度生长和长骨生长板消融。这些结果突出了在骨骼成熟之前抑制病理性骨形成的挑战。
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by debilitating heterotopic ossification (HO). The retinoic acid receptor gamma agonist, palovarotene, and antibody-mediated activin A blockade have entered human clinical trials, but how these therapeutic modalities affect the behavior of pathogenic fibro/adipogenic progenitors (FAPs) is unclear. Using live-animal luminescence imaging, we show that transplanted pathogenic FAPs undergo rapid initial expansion, with peak number strongly correlating with HO severity. Palovarotene significantly reduced expansion of pathogenic FAPs, but was less effective than activin A inhibition, which restored wild-type population growth dynamics to FAPs. Palovarotene pretreatment did not reduce FAPs’ skeletogenic potential, indicating that efficacy requires chronic administration. Although palovarotene inhibited chondrogenic differentiation in vitro and reduced HO in juvenile FOP mice, daily dosing resulted in aggressive synovial joint overgrowth and long bone growth plate ablation. These results highlight the challenge of inhibiting pathological bone formation prior to skeletal maturation.