My laboratory has a long-standing interest in the study of cartilage and bone development. Over the years, we have used cartilage and bone tissues as models to establish important principles in the broader fields of receptor and hypoxia biology.
Brief Summary of Past Major Discoveries
We cloned the human parathyroid hormone (PTH)/PTH related peptide (PTHrP) receptor (PTH/PTHrP), and we discovered that gain-of-function mutations of the PTH/PTHrP receptor cause Jansen Metaphyseal Chondrodysplasia. Lessons from mutant mice we generated using these mutant receptors have strongly influenced our understanding of the role of the PTH/PTHrP receptor in bone, cartilage and hematopoiesis.
HIFs and VHL in tissue development and homeostasis, and in tumorigenesis
Adaptation to low oxygen tension or hypoxia is a critical event in development and tissue homeostasis, and oxygen is not only an indispensable metabolic substrate but also a regulatory signal. Our working hypothesis is that gradients of oxygenation control organ size and shape, and tissue survival, differentiation and homeostasis by regulating activity of the Hypoxia Inducible Factors (HIFs). We are testing this hypothesis in cartilage and bone of genetically modified mice.
Along these lines, we discovered that the murine fetal growth plate displays a gradient of oxygenation with an inner, hypoxic region. We demonstrated that HIF-1 is an in vivo survival factor for hypoxic growth plate chondrocytes, and it is also necessary for in vivo timely differentiation of mesenchymal cells into chondrocytes and for joint development. Moreover, we established that HIF-1 is essential for the development of the nucleus pulposus, which, like the fetal growth plate, is an avascular tissue. Lastly, we proved that the E3 ubiquitin ligase Von Hippel Lindau (VHL) responsible for degradation of HIFs controls size, shape and overall development of endochondral bones, and its loss in limb bud mesenchyme causes severe dwarfism, formation of ectopic cartilage and development of aggressive fibrosis of the synovial joints and of mesenchymal tumors of the soft tissue.
A gradient of oxygenation is also present in the bone marrow, despite its high degree of vascularization. Notably, we discovered that the HIF signaling pathway in osteoblasts can be targeted to augment trabecular bone mass. Furthermore, we provided evidence that osteoblasts are able to produce and secrete erythropoietin (EPO), and thus modulate erythropoiesis, and that HIF-2 controls osteoblastic production of EPO.
We are currently investigating:
1. HIFs in patterning of the skeleton
2. HIFs and reprogramming of metabolism in survival and differentiation of chondrocytes
3. HIFs and EPO in bone development and homeostasis
4. VHL and HIFs in the development of mesenchymal tumors of the soft tissue
- Additional information on my past and current research may be found in my CV, NIH-Bio page and PubMed search of my various publications. Please feel free to contact me to discuss any of my labs research in more detail.