Fig. 8.

Proposed model for Wnt signaling under hypoxia. Under normoxic conditions (A), HIF-α isoforms are targeted for degradation; Mef2 and Smads are recruited to the distal van Buchem enhancer region, where they augment sclerostin expression. Sclerostin is transcribed and secreted, functions in an autonomous fashion and inhibit Wnt binding to Lrp5 or Lrp6. β-catenin is degraded, and there is no transcription of TCF-dependent genes. Under hypoxia (B), HIF-lα isoforms are stabilized and induce HIF-dependent transcription of Vegf, Greml, and Noggin; gremlin and noggin are released from the cell, where they may antagonize BMP function and reduce Smad phosphorylation. Through an unknown mechanism, Mef2 isoforms are excluded from the nucleus and, thus, Sost transcription is reduced. Reductions in sclerostin protein enhance Wnt signaling, thereby stabilizing β-catenin and enabling gene transcription with TCF.