Center for Bone Biology

ATF4 regulate chondrocyte proliferations and differentiation via target Indian Hedgehog transcription.

Weiguang Wang.  Indian hedgehog (Ihh) is the only known morphogen that controls coordination of chondrogenesis and osteogenesis.  Surprisingly, our understanding of the regulation of Ihh itself is incomplete, particularly at the transcriptional level.  Here we show that ATF4 acted as a transcriptional regulator of Ihh.  Deletion of Atf4 in mice led to dwarfism in addition to a severe osteoporotic phenotype.  By examining morphological and molecular markers of wild-type (wt) and Atf4-/- growth plates, we found that the hypertrophic chondrocyte zone of Atf4-/- growth plates was expanded, proliferation of the chondrocytes in the Atf4-/- growth plates was decreased compared to their littermate controls.  In addition, the expression of Ihh and other Ihh downstream targests, such as Pthrp and Vegf, was markedly decreased in the Atf4-/- growth plates by in situ hybridization and Northern blot analysis.  Molecularly, we found that ATF4 bound directly to the promoter sequence of Ihh and transactivates Ihh-reporter gene in cells.  Furthermore, epitopically expression of ATF4 in chondrocyte cell line increased endogenous expression of Ihh and PTHrP mRNAs.  Together, our study establishes that Ihh is a transcriptional target of ATF4 in the control of long bone growth by regulating chondrocyte proliferation and differentiation.