Hedgehog Activation Regulates Human Osteoblastogenesis

• Published in: Stem cell reports Vol. 15; no. 1; pp. 125 - 139
• Main Authors: Onodera, Shoko, Saito, Akiko, Hojo, Hironori, Nakamura, Takashi, Zujur, Denise, Watanabe, Katsuhito, Morita, Nana, Hasegawa, Daigo, Masaki, Hideki, Nakauchi, Hiromitsu, Nomura, Takeshi, Shibahara, Takahiko, Yamaguchi, Akira, Chung, Ung-il, Azuma, Toshifumi, Ohba, Shinsuke
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 14.07.2020; Elsevier
• Subjects: calcification; fibrous dysplasia; Gorlin syndrome; hedgehog pathway; McCune-Albright syndrome; osteogenesis; patient-specific iPSC; McCune-Albright syndrome; hedgehog pathway; Gorlin syndrome; fibrous dysplasia; osteogenesis; calcification; patient-specific iPSC
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2020.05.008

Two genetic diseases, Gorlin syndrome and McCune-Albright syndrome (MAS), show completely opposite symptoms in terms of bone mineral density and hedgehog (Hh) activity. In this study, we utilized human induced pluripotent stem cell (iPSC)-based models of the two diseases to understand the roles of Hh signaling in osteogenesis. Gorlin syndrome-derived iPSCs showed increased osteoblastogenesis and mineralization with Hh signaling activation and upregulation of a set of transcription factors in an osteogenic culture, compared with the isogenic control. MAS-specific iPSCs showed poor mineralization with low Hh signaling activity in the osteogenic culture; impaired osteoblastogenesis was restored to the normal level by treatment with an Hh signaling-activating small molecule. These data suggest that Hh signaling is a key controller for differentiation of osteoblasts from precursors. This study may pave a path to new drug therapies for genetic abnormalities in calcification caused by dysregulation of Hh signaling. •iPSCs from patients with Gorlin syndrome showed enhancement of osteoblastogenesis•Distinct transcription factors, including FOXO1 were induced in Gorlin iPSCs•McCune-Albright syndrome-specific iPSCs demonstrated a decrease in Hh activity•SAG treatment rescued immature calcification in MAS-specific iPSCs Ohba and Azuma focused on two genetic diseases, Gorlin syndrome and McCune-Albright syndrome, which demonstrated opposite calcification phenotypes. A small compound that activates Hh pathway normalized calcification in McCune-Albright syndrome iPSCs. This strategy may be useful for the treatment of other diseases, including solitary fibrous dysplasia or some types of osteoporosis.