Patched1 haploinsufficiency increases adult bone mass and modulates Gli3 repressor activity
Patched1 haploinsufficiency increases adult bone mass and modulates Gli3 repressor activity
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DOI：
10.1016/j.devcel.2008.03.007
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发表时间：
2008-05-01
影响因子：
11.8
通讯作者：
Chung, Ung-il
中科院分区：
文献类型：
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作者：
Ohba, Shinsuke;Kawaguchi, Hiroshi;Chung, Ung-il
Hedgehog (Hh)- patche1 （Ptch1）信号在多种发育过程中发挥重要作用，但对其在出生后体内平衡中的作用知之甚少。在这里，我们证明了Hh-Ptch1信号对出生后骨稳态的调节。Ptch1缺失（Ptch1(+/-)）小鼠和瘤状基底细胞癌综合征患者在成人中表现出高骨量。在培养中，Ptch1（+/-）细胞表现出加速的成骨细胞分化，增强对矮子相关转录因子2 （Runx2）的反应性，减少Gli3抑制因子形式的产生（Gli3rep）。Gli3rep在体外抑制Runx2的DNA结合，提示一种机制可能有助于Ptch1杂合子的骨表型。此外，全身给予Hh信号抑制剂环巴胺可降低成年小鼠的骨量。这些数据提供了Hh-Ptch1信号在出生后骨稳态中起关键作用的证据，并指出Hh-Ptch1信号是治疗骨质疏松症的潜在分子靶点。
Hedgehog (Hh)-Patched1 (Ptch1) signaling plays essential roles in various developmental processes, but little is known about its role in postnatal homeostasis. Here, we demonstrate regulation of postnatal bone homeostasis by Hh-Ptch1 signaling. Ptch1-deficient (Ptch1(+/-)) mice and patients with nevoid basal cell carcinoma syndrome showed high bone mass in adults. In culture, Ptch1(+/-) cells showed accelerated osteoblast differentiation, enhanced responsiveness to the runt-related transcription factor 2 (Runx2), and reduced generation of the repressor form of Gli3 (Gli3rep). Gli3rep inhibited DNA binding by Runx2 in vitro, suggesting a mechanism that could contribute to the bone phenotypes seen in the Ptch1 heterozygotes. Moreover, systemic administration of the Hh signaling inhibitor cyclopamine decreased bone mass in adult mice. These data provide evidence that Hh-Ptch1 signaling plays a crucial role in postnatal bone homeostasis and point to Hh-Ptch1 signaling as a potential molecular target for the treatment of osteoporosis.