Wnt/β-catenin signaling interacts differentially with Ihh signaling in controlling endochondral bone and synovial joint formation

Both the Wnt/β-catenin and lhh signaling pathways play essential roles in crucial aspects of endochondral ossification: osteoblast differentiation, chondrocyte proliferation and hypertrophy. To understand the genetic interaction between these two signaling pathways, we have inactivated the β-catenin gene and upregulated lhh signaling simultaneously in the same cells during endochondral skeletal development using β-catenin and patched 1 floxed alleles. We uncovered previously unexpected roles of lhh signaling in synovial joint formation and the essential function of Wnt/β-catenin signaling in regulating chondrocyte survival. More importantly, we found that Wnt and lhh signaling interact with each other in distinct ways to control osteoblast differentiation, chondrocyte proliferation, hypertrophy, survival and synovial joint formation in the developing endochondral bone. β-catenin is required downstream of lhh signaling and osterix expression for osteoblast differentiation. But in chondrocyte survival, β-catenin is required upstream of lhh signaling to inhibit chondrocyte apoptosis. In addition, lhh signaling can inhibit chondrocyte hypertrophy and synovial joint formation independently of β-catenin. However, there is a strong synergistic interaction between Wnt/ β-catenin and lhh signaling in regulating synovial joint formation.