I have a long-standing interest in the study of cartilage and bone development. Over the years, I have used cartilage and bone tissues as models to establish essential principles in the broader fields of G-protein coupled receptors and hypoxia biology.
As a member of Dr. Harald Jueppner’s laboratory at MGH-Harvard Medical School, I cloned the human PTH/PTHrP receptor (PTHR1) and its gene, and discovered that gain-of-function mutations of PTHR1 cause Jansen Metaphyseal Chondrodysplasia (JMC), a severe form of short-limbed dwarfism associated to hypercalcemia (link to paper). JMC has been one of the first examples in the literature of a human disease being caused by a constitutively active G-protein coupled receptor. Analysis of mutant mice I generated using those mutations have contributed to shape up our current understanding of the role of osteoblastic PTHR1 in skeletal development and homeostasis, and hematopoiesis (link to paper 1, paper 2, paper 3, paper 4).
Next, as an independent investigator I pioneered the notion that gradients of oxygen control tissue morphogenesis during skeletal development (link to paper). Oxygen is not only an essential metabolic substrate in numerous enzymatic reactions, including mitochondrial respiration, but also a regulatory signal. My laboratory studies the role of hypoxia-driven pathways in skeletal development with the overall goal of unveiling both novel aspects of the cellular adaptation to hypoxia and new avenues for the treatment of cartilage and bone diseases. We use genetically modified mice as a model organism and we analyze their phenotypes with a variety of in vivo and ex-vivo assays.
HIF1, mitochondria and the reprogramming of metabolism in skeletal development
Studying the fetal growth plate, I was intrigued by its avascularity; this simple observation led me to discover that the hypoxia-driven pathways are essential in skeletal development. I established that the murine fetal growth plate displays a gradient of oxygenation with an inner, hypoxic region (link to paper). Furthermore, I provided evidence that HIF1, which is a transcription factor and a key mediator of the cellular adaptation to hypoxia, is a survival factor for growth plate chondrocytes (link to paper). My laboratory also demonstrated that HIF1 is necessary for timely differentiation of mesenchymal cells into chondrocytes and for joint development in vivo (link to paper). HIF1 promotes glycolysis and lactate production but represses mitochondrial respiration. Along those lines, we recently showed that the HIF1-dependent impairment of mitochondrial respiration and thereby oxygen consumption protects growth plate chondrocytes that are physiologically hypoxic from lethal intracellular anoxia (link to paper).
My laboratory is currently investigating how the interplay between mitochondria and HIF1-dependent reprogramming of metabolism controls skeletal development (R01 AR074079, Dr. Schipani PI).
HIF2 and the control of bone mass accrual and homeostasis
My laboratory also recently demonstrated that loss of HIF2 in mesenchymal progenitors increases bone mass accrual by promoting bone formation without affecting bone resorption. HIF2 is another crucial mediator of the cellular adaptation to hypoxia (link to paper 1, paper 2).
We are currently investigating whether pharmacological inhibition of HIF2 phenocopies the genetic experiment. HIF2 can be selectively inhibited by small molecules that are in clinical trials in patients with renal carcinoma. Inhibiting HIF2 could represent a therapeutic approach for the treatment of the low bone mass observed in chronic diseases, osteoporosis or aging. Additionally, we are using unbiased approaches to establish how the loss of osteoblastic HIF2 promotes bone formation (R01 AR073022, Dr. Schipani PI).
HIF1, mitochondria and the reprogramming of metabolism in somitogenesis
We recently established that HIF1 is critical for spine development as its loss in the presomitic mesoderm impairs somitogenesis and causes spine and rib malformations that closely mimic those observed in patients with Jarcho-Levin Syndrome, a rare form of spondylothoracic dysplasia (Manuscript in preparation).
We are currently investigating whether the impairment of somitogenesis secondary to loss of HIF1 is due to dysregulation of glycolysis and mitochondrial function in the presomitic mesoderm (R01 in preparation, Dr. Schipani PI).
Role of the hypoxia-driven pathways in the pathogenesis of fibroblastic tumors and cartilage regeneration
Lastly, we showed that continuous activation of hypoxia-driven pathways in mesenchymal progenitors of the limb bud is sufficient to generate ectopic cartilage in the soft tissue surrounding the growth plate. It also causes aggressive fibrosis of the synovial joints, formation of fibroblastic tumors in proximity of skeletal elements, and dwarfism (link to paper). The dwarfism is a consequence of both impaired proliferation and delayed hypertrophy of growth plate chondrocytes (link to paper 1, paper 2).
My laboratory is currently investigating the role of the hypoxia signaling pathway in the onset of fibroblastic tumors of the soft tissue (Departmental funds).
Moreover, in collaboration with Dr. Peter Ma at UMICH-Dental School, we are testing the hypothesis that transient and local activation of the HIFs in vivo may contribute to heal articular cartilage defects by promoting chondrogenesis and inhibiting chondrocyte hypertrophy without causing significant synovial fibrosis (R01 submitted, Dr. Ma PI, Dr.Schipani Co-Investigator).
Jansen Metaphyseal Chonrodysplasia
My laboratory is currently collaborating with my former mentor Dr. Harald Jueppner at MGH-Harvard Medical School to identify potential therapeutic avenues for the treatment of JMC (R01 DK113039, Dr. Jueppner PI, Dr. Schipani Co-Investigator).
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 research in more detail.