Professor in Cell and Developmental Biology, University of Massachusetts Medical School
Associate Professor of Biological Chemistry, Harvard Medical School, Boston
Senior Research Associate, Department of Orthopaedic Surgery, Children's Hospital Medical Center, Boston
Post-doctoral training: National Institutes of Health.
Ph.D., Boston University School of Medicine
Skeletal Development, Bone Biology and PathologyBone tissue functions as a mechanically responsive structural component of the body and as a major organ essential for maintaining calcium and phosphate homeostasis. The skeleton is the target of numerous human genetic disorders and numerous mouse models have identified new regulatory pathways that affect the skeleton. As a normal process of aging and hormonal changes after the menopause, skeletal mass can decrease by as much as 30% leading to bone fracture and compromised quality of life in the elderly population. Historically the laboratory has addressed molecular mechanisms regulating formation and mineralization of bone by osteoblasts and turnover of bone tissue by osteoclasts, the bone resorbing cells. We are defining the key regulatory events for the progressive differentiation of osteoprogenitor stem cells to osteogenic cells by identifying epigenetic, transcriptional and microRNA regulation of tissue-specific genes.
The skeleton is also a target of metabolic diseases including diabetes, neuropathys, hormone disorders and mal absorption syndromes), as well as metastatic cancers. A focus of our lab is establishing the epigenetic and genetic modifications in primary tumor cells that mediate homing to bone and responsiveness of tumor cells tot the bonemicroenvironment that result is destruction of the bone. Translational approaches to block these activities are being pursued through microRNA delivery to tumors and bone.
The laboratory uses a wide range of experimental approaches including in vitro molecular analyses , genomic profiling (RNA-Seq, Deep-Seq, ChIP-Seq and miRNA) and in vivo mouse models including genetic mutations, fracture healing and tumor forming models of prostate and breast cancer.
Areas of current investigation for graduate and MD/PhD students and postdoctoral fellows include:
1. Combinatorial Control Mechanisms for Skeletal Development
This laboratory is defining a regulatory network of developmental factors with a focus on three major pathways critical for skeletal pattern formation, early embryonic bone development, and osteoblast differentiation involving the bone morphogenetic protein (BMP) family, Wnt signaling pathway and their interface with bone essential transcription factors, Runx2/Cbfa, Hoxa10 and the homeodomain factors, Msx2, Dlx3 and Dlx5. We are characterizing the formation of multicomponent transcriptional complexes that modify the chromatin, contain transcriptional mediators of signaling pathways and facilitate activationand repression of genes to regulate their temporal expression during osteogenesis in vivoand stages during development of the osteoblast phenotype from stem cell to the mature osteocyte in a mineralized tissue.
2. Characterization of Mouse Phenotypes Resulting from Mutation of Bone Related Genes
Mutation of any gene can lead to primary or secondary effects on the skeleton. Screening for this phenotype is done by several rapid techniques ( high resolution radiography and micro computer tomography), followed by histological, ex vivo cellular( culturing osteoblasts, bone marrow cells and osteoclasts for defects in differentiation), as well as molecular analyses. Our current mouse models are focused on mutations in bone essential transcription factors, loss-of-function of microRNAs and Wnt inhibitors. Our translational goal is to develop an anabolic strategy for maintaining bone mass during aging age and inducing a rapid increase for when severe bone loss has already occurred.
3. Cancer Cell Biology in the Bone Microenvironment
The end stage of breast and prostate cancer is metastasis to bone, with very poor prognosis with nearly 70% mortality within a year. Cancer cells cause destruction of the bone, resulting in fractures and severe pain. Understanding the mechanisms which induce metastasis of the primary cancer cell to the bone environment needs to be addressed. We have identified high expression levels of the Runx2 transcription factor in metastatic breast and prostate cancer cell lines. Runx target genes in the cancer cell include the entire class of matrix metalloproteinases characterized for their role in tissue invasion, the vascular endothelial growth factor, a potent angiogenic factor involved as a primary event in tumor growth and several cell growth and osteoblastic genes expressed in the bone environment that allow for tumor growth The cancer cell responds to TGFB and BMP growth factors in the bone extracellular matrix and stimulates bone resorbing cells thorugh activation of PTHrP, Ihh and Gli pathways. We are currentlyfocusing on microRNA regulation of bone metastasis for developing translational strategies.