title: Indian Hedgehog signalling triggers Nkx3.2 protein degradation during chondrocyte maturation.
abstract: The Ihh (Indian Hedgehog) pathway plays an essential role in facilitating chondrocyte hypertrophy and bone formation during skeletal development. Nkx3.2 (NK3 homeobox 2) is initially induced in chondrocyte precursor cells, maintained in early-stage chondrocytes and down-regulated in terminal-stage chondrocytes. Consistent with these expression patterns, Nkx3.2 has been shown to enhance chondrocyte differentiation and cell survival, while inhibiting chondrocyte hypertrophy and apoptosis. Thus, in the present study, we investigated whether Nkx3.2, an early-stage chondrogenic factor, can be regulated by Ihh, a key regulator for chondrocyte hypertrophy. We show that Ihh signalling can induce proteasomal degradation of Nkx3.2. In addition, we found that Ihh can suppress levels of Lrp (low-density-lipoprotein-receptor-related protein) (Wnt co-receptor) and Sfrp (secreted frizzled-related protein) (Wnt antagonist) expression, which, in turn, may selectively enhance Lrp-independent non-canonical Wnt pathways in chondrocytes. In agreement with these findings, Ihh-induced Nkx3.2 degradation requires Wnt5a, which is capable of triggering Nkx3.2 degradation. Finally, we found that Nkx3.2 protein levels in chondrocytes are remarkably elevated in mice defective in Ihh signalling by deletion of either Ihh or smoothened. Thus these results suggest that Ihh/Wnt5a signalling may play a role in negative regulation of Nkx3.2 for appropriate progression of chondrocyte hypertrophy during chondrogenesis.
authors.affiliation: Department of Biochemistry, Yonsei University College of Life Science and Biotechnology, 262 Seongsanno Seodaemoon-Gu, Seoul, 120-749, Republic of Korea.
authors.forename: Seung-Won
authors.initials: SW
authors.lastname: Choi
authors.forename: Da-Un
authors.initials: DU
authors.lastname: Jeong
authors.forename: Jeong-Ah
authors.initials: JA
authors.lastname: Kim
authors.forename: Boyoung
authors.initials: B
authors.lastname: Lee
authors.forename: Kyu Sang
authors.initials: KS
authors.lastname: Joeng
authors.forename: Fanxin
authors.initials: F
authors.lastname: Long
authors.forename: Dae-Won
authors.initials: DW
authors.lastname: Kim
mesh_terms: D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology*; D017931:DNA Primers; D053823:Hedgehog Proteins / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D059748:Proteolysis; D015398:Signal Transduction
chemical_list: D017931:DNA Primers; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins