HIFs in Fibroblastic Tumors
We are looking at the role of the HIFs in the onset of fibroblastic tumors of the soft tissue.
We also showed that continuous activation of hypoxia-driven pathways in mesenchymal progenitors of the limb bud causes aggressive fibrosis of the synovial joints and the formation of fibroblastic tumors in the proximity of skeletal elements. We are currently investigating the role of the hypoxia signaling pathway in the onset of fibroblastic tumors of the soft tissue (UPenn-Start up funding).
Fibrosis and hypoxia-inducible factor-1α-dependent tumors of the soft tissue on loss of von Hippel-Lindau in mesenchymal progenitorsView Publication
The hypoxia-inducible factor (Hif)-1α (Hif-1α) and Hif-2α (Epas1) have a critical role in both normal development and cancer. von Hippel Lindau (Vhl) protein, encoded by a tumor suppressor gene, is an E3 ubiquitin ligase that targets Hif-1α and Epas1 to the proteasome for degradation. To better understand the role of Vhl in the biology of mesenchymal cells, we analyzed mutant mice lacking Vhl in mesenchymal progenitors that give rise to the soft tissues that form and surround synovial joints. Loss of Vhl in mesenchymal progenitors of the limb bud caused severe fibrosis of the synovial joints and formation of aggressive masses with histologic features of mesenchymal tumors. Hif-1α and its downstream target connective tissue growth factor were necessary for the development of these tumors, which conversely still developed in the absence of Epas1, but at lower frequency. Human tumors of the soft tissue are a very complex and heterogeneous group of neoplasias. Our novel findings in genetically altered mice suggest that activation of the HIF signaling pathway could be an important pathogenetic event in the development and progression of at least a subset of these tumors.
Loss of VHL in mesenchymal progenitors of the limb bud alters multiple steps of endochondral bone developmentView Publication
- 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.
Deletion of Vhlh in chondrocytes reduces cell proliferation and increases matrix deposition during growth plate developmentView Publication
The von Hippel Lindau tumor suppressor protein (pVHL) is a component of a ubiquitin ligase that promotes proteolysis of the transcription factor hypoxia-inducible-factor 1α (HIF1α), the key molecule in the hypoxic response. We have used conditional inactivation of murine VHL (Vhlh) in all cartilaginous elements to investigate its role in endochondral bone development. Mice lacking Vhlh in cartilage are viable, but grow slower than control littermates and develop a severe dwarfism. Morphologically, Vhlh null growth plates display a significantly reduced chondrocyte proliferation rate, increased extracellular matrix, and presence of atypical large cells within the resting zone. Furthermore, stabilization of the transcription factor HIF1α leads to increased expression levels of HIF1α target genes in Vhlh null growth plates. Lastly, newborns lacking both Vhlh and Hif1a genes in growth plate chondrocytes display essentially the same phenotype as Hif1a null single mutant mice suggesting that the Vhlh null phenotype could result, at least in part, from increased activity of accumulated HIF1α. This is the first study reporting the novel and intriguing findings that pVHL has a crucial role in endochondral bone development and is necessary for normal chondrocyte proliferation in vivo.