Ohba Shinsuke, Kawaguchi Hiroshi, Kugimiya Fumitaka, Ogasawara Toru, Kawamura Naohiro, Saito Taku, Ikeda Toshiyuki, Fujii Katsunori, Miyajima Tsuyoshi, Kuramochi Akira, Miyashita Toshiyuki, Oda Hiromi, Nakamura Kozo, Takato Tsuyoshi, Chung Ung-Il
Department of Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Dev Cell. 2008 May;14(5):689-99. doi: 10.1016/j.devcel.2008.03.007.
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.
刺猬信号通路（Hh）- patched1（Ptch1）信号在各种发育过程中发挥着重要作用，但对其在出生后体内稳态中的作用知之甚少。在此，我们证明了Hh - Ptch1信号对出生后骨稳态的调节作用。Ptch1基因缺陷（Ptch1+/-）小鼠和痣样基底细胞癌综合征患者在成年后表现出高骨量。在培养过程中，Ptch1+/-细胞显示出成骨细胞分化加速、对与矮小相关转录因子2（Runx2）的反应性增强以及Gli3阻遏形式（Gli3rep）的生成减少。Gli3rep在体外抑制Runx2与DNA的结合，提示了一种可能导致Ptch1杂合子中所见骨表型的机制。此外，全身性给予Hh信号抑制剂环杷明可降低成年小鼠的骨量。这些数据证明Hh - Ptch1信号在出生后骨稳态中起关键作用，并指出Hh - Ptch1信号是治疗骨质疏松症的潜在分子靶点。
