Loss of VHL in mesenchymal progenitors of the limb bud alters multiple steps of endochondral bone development

• Published in: Developmental biology Vol. 393; no. 1; pp. 124 - 136
• Main Authors: Mangiavini, Laura, Merceron, Christophe, Araldi, Elisa, Khatri, Richa, Gerard-O’Riley, Rita, LeShan Wilson, Tremika, Rankin, Erinn B., Giaccia, Amato J., Schipani, Ernestina
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2014
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; Cell Differentiation - genetics; Cell Hypoxia; Cell Proliferation; Cells, Cultured; Chondrogenesis - genetics; Chondrogenesis - physiology; Endochondral bone development; Growth Plate - embryology; Growth Plate - growth & development; Hypoxia Inducible Factor; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Limb bud mesenchyme; Limb Buds - cytology; Mesenchymal Stromal Cells - cytology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Osteogenesis - genetics; Von Hippel-Lindau Tumor Suppressor Protein - genetics; Von Hippel-Lindau Tumor Suppressor Protein - physiology; Von Hippel–Lindau; Von Hippel–Lindau; Endochondral bone development; Limb bud mesenchyme; Hypoxia Inducible Factor
• ISSN: 0012-1606; 1095-564X
• DOI: 10.1016/j.ydbio.2014.06.013

Adaptation to low oxygen tension (hypoxia) is a critical event during development. The transcription factors Hypoxia Inducible Factor-1α (HIF-1α) and HIF-2α are essential mediators of the homeostatic responses that allow hypoxic cells to survive and differentiate. Von Hippel–Lindau protein (VHL) is the E3 ubiquitin ligase that targets HIFs to the proteasome for degradation in normoxia. We have previously demonstrated that the transcription factor HIF-1α is essential for survival and differentiation of growth plate chondrocytes, whereas HIF-2α is not necessary for fetal growth plate development. We have also shown that VHL is important for endochondral bone development, since loss of VHL in chondrocytes causes severe dwarfism. In this study, in order to expand our understanding of the role of VHL in chondrogenesis, we conditionally deleted VHL in mesenchymal progenitors of the limb bud, i.e. in cells not yet committed to the chondrocyte lineage. Deficiency of VHL in limb bud mesenchyme does not alter the timely differentiation of mesenchymal cells into chondrocytes. However, it causes structural collapse of the cartilaginous growth plate as a result of impaired proliferation, delayed terminal differentiation, and ectopic death of chondrocytes. This phenotype is associated to delayed replacement of cartilage by bone. Notably, loss of HIF-2α fully rescues the late formation of the bone marrow cavity in VHL mutant mice, though it does not affect any other detectable abnormality of the VHL mutant growth plates. Our findings demonstrate that VHL regulates bone morphogenesis as its loss considerably alters size, shape and overall development of the skeletal elements. •VHL is a key regulator of endochondral bone development and bone morphogenesis.•Loss of VHL does not alter the transition from mesenchymal cells into chondrocytes.•Loss of VHL impairs chondrocyte proliferation and delays hypertrophy.•Loss of VHL results in bone deformities in selective sites.•Loss of VHL causes chondrocyte death in postnatal growth plates.