Yingzi Yang , PhD, Professor of Developmental Biology
The Yang lab uses molecular, cellular, genetic and genomic approaches to investigate critical roles of cell signaling in embryonic morphogenesis and adult physiology. We mainly focus on the mammalian limb, skeleton and liver, and we are exploiting these systems to explore human biology and address the underlying pathological mechanisms of diseases including cancer.
Cell-cell signaling plays essential and pivotal roles in both development and physiology. We are particularly interested in the Wnt, Hedgehog and Hippo signaling pathways that are evolutionarily conserved, act repetitively in different systems and regulate a diverse array of biological processes. Mutations in components of these signaling pathways cause devastating birth defects, degenerative disorders and cancer.
The vertebrate limb and skeleton provide a great system for us to understand morphogenesis and signaling interactions. Early patterning signals, which include Hedgehogs, Wnts, FGFs, and TGF-superfamily members, provide temporal and spatial information to instruct skeletal anlagen formation, long before overt skeletal morphogenesis. These signaling pathways also play major roles in regulating cell fates, proliferation and polarity in the formed skeletal system. Our previous work has provided insights into several fundamental aspects of tissue and organ morphogenesis in the limb and skeleton and tumor formation in the liver.
Our current efforts are divided into three major projects:
- Understand the role of signaling pathways in cell fate determination. We are investigating the molecular and cellular mechanisms whereby the Gs and Hedgehog signaling pathways regulate fate choices of differentiating mesenchymal progenitor/stem cells under both physiological and pathological conditions.
- Understand the function of directional information in development and disease. We are investigating the regulatory mechanisms whereby Wnt signaling controls planar cell polarity (PCP) in various aspects of embryonic morphogenesis, skeletal development and homeostasis.
- Understand the molecular and cellular mechanism underlying mechanotransduction in the skeletal system. The musculoskeletal system generates and is also highly regulated by mechanic forces. We are investigating the roles of the Wnt and Hippo signaling pathways in mediating the effects of mechanotransduction in both development, physiology and regeneration in the liver and skeleton.
Giuseppe Intini , DDS, PhD, Assistant Professor of Oral Medicine, Infection, and Immunity
The research in the Intini laboratory, or the intinilab, as we like to call it, focuses on the biology of the adult skeletal stem cells. We use mouse genetics and in vivo imaging to describe the location of these stem cells within the intramembranous bone, their contribution to tissue repair, the effects of aging on these cells, and the molecular mechanisms that control their "stemness”. Similar to what Dr. Yamanaka has described for the iPS cells, we believe that a limited number of genes expressed by adult skeletal stem cells confer the stemness quality to these cells. With the final goal of translating our research into clinically useful information we therefore aim to identify these genes and understand the influence that cellular location or aging has on their expression.
Another project at its initial stages at the intinilab focuses on the role of skeletal stem cells and cancer stem cells in development and maintenance of osteosarcoma. In this project we aim to trace the stem cells and identify mechanisms that may prevent metastasis, the ultimate cause of death in children with osteosarcoma.
Current laboratory members:
Katarzyna Wilk, B.Sc. Biochemistry, Research assistant
Courtney M. Lombardo, B.Sc. Biology, Visiting Fellow
Luke J. Mortensen, Ph.D., Postdoctoral fellow
Sasan Ghaffarigarakani, D.D.S., Resident HSDM AGE Periodontics
Hossein S. Bassir, D.D.S., Resident HSDM AGE Periodontics
Donald B. Giddon , DMD, PhD, Clinical Professor of Developmental Biology
Dr. Giddon’s research involves the psychophysical determination of the anthropometric bases of subjective judgments of facial appearance. Other areas of research as a biostatistician include lateralization of pain, other pathology, and perception; and the ratio of dental morphology to the second and fourth digit length.
A new educational project under way includes changing the designation of dentist to oral physician and reevaluating the training of postgraduate master’s- and doctoral-degree students.
Faculty research collaborator
Nina Anderson, PhD
Elsbeth Kalenderian , DDS, MPH, PhD, Chair, Department of Oral Health Policy and Epidemiology; Chief of Quality, Harvard Dental Center; Associate Professor of Oral Health Policy and Epidemiology
As a clinical researcher, Dr. Kalenderian is currently involved in research focused on the electronic health record, Patient Safety, and received an American Dental Award for research that seeks to predict future (clinical years) performance of dental students through assessing their performance in a first-year, longitudinal course that focuses on the relationship between patient and provider.
Lin Xu , MD, PhD, Instructor in Developmental Biology
The Xu laboratory focuses on the pathogenesis of temporomandibular joint (TMJ) degeneration, which affects millions of people around the world. TMJ is the most used and unique joint in human body. Articular cartilage of TMJ is fibrocartilage, which is different from other joints. A question has been raised as to whether the molecular basis underlying TMJ degeneration is similar to or different from other joints. To address this question, we established a surgically induced mouse model and identified two genetic mutant mouse models for study of TMJ degeneration. We have been investigating molecular mechanisms of TMJ degeneration by use of these mouse models. Results from our study will ultimately provide valuable information in search of novel therapeutic protocols for the prevention and treatment of TMJ disorders.
John Da Silva
John D. Da Silva , DMD, MPH, ScM, Vice Dean; Associate Professor, Department of Restorative Dentistry and Biomaterials Sciences; Medical Director, Harvard Dental Center
Dr. Da Silva conducts clinical research. His research interest includes translational research in optics and color science in dentistry. He is also involved with the Children’s Hospital Center for Adolescent Substance Abuse Research to develop an Internet/Intranet-based motivational enhancement therapy (iMET) program for adolescents that can be used in dental and medical offices to target tobacco, alcohol, and drug use.
Shigemi Ishikawa Nagai , PhD, DDS, MSD, Associate Professor of Restorative Dentistry and Biomaterials Sciences, Director of Predoctoral Prosthodontics
The Nagai Lab combines basic science with clinical and developmental research. Research is focused on color science, soft tissue esthetics in dental implants, and early caries detection, as well as a project involving osteoinductive peptides found by a new biopanning method.
Development of Early Caries Detection System
The Nagai lab has been dedicated to the development of an early caries detection system using near-infrared fluorescence. The goal of this study is to put an end to “Drill, Fill and Bill” dentistry and to enhance natural healing by remineralization. Our preliminary in vitro studies confirm that the sensitivity of this new system is as high as three times that of dental radiography. Also, the odds of underestimation errors (i.e. missing early caries) is reduced by 97% in comparison to dental radiography. The current stage of the development is clinical assessment of the feasibility of a prototype device.
Color Science in Dentistry
A dental spectrophotometer was developed in collaboration with the Olympus Corporation. This is the only dental spectrophotometer providing both numerical data and natural images. Clinical research has been done at HSDM resulting in the publication of several papers.
The next step will be a multi center study employing this dental spectrophotometer aimed at developing a computer color matching system for dental ceramic restorations.
Application of Novel Osteoinductive Peptides for Dental Implants
Novel peptides screened by a new biopaning system will be assessed for osteoinduction ability for a use with titanium dental implants.
Soft Tissue Esthetics at Implant Sites
Colored neck dental implants have been developed with supported from the ITI Research Foundation between 2003-2008. These implants improve the grayish color shine through effects on gingival tissue in anterior dental implant sites.
Arthur Garvey Research
Dr. Garvey has made major contributions to efforts in the fields of health promotion and disease prevention. His interests are in the development of new treatments to help addicted smokers quit smoking and maintain permanent smoking abstinence.
German Gallucci , Dr. med. dent., PhD, Interim Department Chair and Assistant Professor of Restorative Dentistry; Director, Division of Regenerative and Implant Sciences
Dr. Gallucci actively participates in clinical and translational research related to Fixed Prosthodontics, Oral Implantology, and applied Digital Dental Technology. He is the Principal Investigator (PI) of the Oral Implantology clinical research team in the Division of Regenerative and Implant Sciences, Harvard School of Dental Medicine.
Vicki Rosen , PhD, Chair and Professor of Developmental Biology
Bone morphogenetic proteins (BMPs), members of the TGFβ gene superfamily, were first identified as potential bone-repair agents. We now know that, along with the bone inductive activity that gave BMPs their name, they are involved in the development of nearly all vertebrate organ systems and tissues, where they play a central role by affecting cell proliferation, differentiation, and apoptosis. The activity of these locally acting factors is tightly controlled, and increasing or decreasing BMP signaling can have significant physiological effects throughout the lifetime of an organism. Using molecular, cellular, and genetic approaches in frogs, chicks, and mice, work in our laboratory is currently focused on three areas of research:
1. What role do individual BMPs play in the formation and maintenance of musculoskeletal tissues and structures? To answer this question, we developed transgenic mice in which we can control the temporal and spatial expression of BMPs and are using these mice to distinguish between the requirement for BMP activity and the need for specific BMPs.
2. How is BMP signaling regulated by extracellular matrix components found in musculoskeletal tissues? BMP-3, the major BMP component of bone matrix, antagonizes the osteogenic activity of other BMPs. This observation identifies a new way to modulate BMP signaling, and suggests that bone matrix may play an important role in the control of bone mass.
3. Can an understanding of the roles of BMPs during embryogenesis be used to generate novel tissue-repair strategies? Recombinant human BMP-2 is currently used during orthopedic surgery as a replacement for bone grafts. Might other BMPs have analogous properties for repair of other musculoskeletal tissues?
Laura W. Gamer
Linda Ross Phone 617-432-5806
Bjorn R. Olsen , MD, PhD, Dean for Research and Professor of Developmental Biology; Hersey Professor of Cell Biology
The Olsen laboratory studies skeletal and vascular morphogenesis, growth, and remodeling/repair. Work is currently directed at three project areas.
In the first project, we are studing skeletal morphogenesis and growth. We are interested in genes that control differentiation of mesenchymal cells to chondrocytes and osteoblasts, the control of spatial patterns of mesenchymal condensations during skeletal development and tooth formation, the molecular mechanisms controlling the formation of ossification centers, the regulation of proliferation and differentiation of chondrocytes in growth plates, and molecular mechanisms responsible for accrual of bone mass and remodeling of the vertebrate skeleton in response to mechanical stress. In addition to using knock-out, knock-in, and conditional knock-out mice in studies of specific genes, we make extensive use of genetic approaches in mice and humans. This includes mapping of inherited disorders, gene identification, and mutation detection.
In the second project, we are investigating the molecular basis for vascular morphogenesis, using a combination of human genetics of vascular tumors and malformations and studies of cells in culture. In addition, we are studying mice with inactivated alleles for collagens that are expressed in vascular cells, and using conditional knock-out techniques to inactivate VEGF and its receptors in mice.
In the third project, we are studying genetic causes of degenerative joint disease (osteoarthritis) in humans and mice. The approach involves identification of mutations responsible for early-onset osteoarthritis as part of inherited osteochondrodysplasias and cellular/molecular analyses of pathogenetic mechanisms.
Postdoctoral research fellows
Donald J. Glotzer
Yulia Pittel, 617-432-2359
Beate Lanske , PhD, Professor of Oral Medicine, Infection, and Immunity, Associate Professor in Medicine, MGH and Harvard Medical School
The Lanske Lab researches the endocrine regulation of mineral ion homeostasis and skeletogenesis. In vivo research requires the use of a wide variety of animal models and molecular biology techniques to answer complex questions. In the Lanske Lab several knockout mice were generated and are currently being used, often in combination with each other and with mice from collaborating groups. The use of transgenic mouse lines harboring the CRE-LoxP system to alter gene expression in specific tissues at specific ages is part of the in vivo investigations. New innovative animal models are being established, such as retroviral mouse lines to study the interaction of genes in specific tissues. In addition to mice, in vitro analyses using various cell lines and primary cell and organ cultures are being performed in the lab. For specific questions, chick embryos are used to study developmental aspects of the genes as well.
A key focus of the Lanske Lab has been, and continues to be, FGF-23, a circulating phosphaturic factor produced in osteoblasts, osteocytes, cementoblasts, and odontoblasts. FGF-23 inhibits renal phosphate reabsorption and vitamin D synthesis, thus playing a key role in phosphate homeostasis. Mutations in FGF-23 and genes that regulate its expression and activation have been linked to several disease processes, including autosomal dominant hypophosphatemic rickets (ADHR), oncogenic osteomalacia (OOM) and X-linked hypophosphatemia (XLH), autosomal recessive hypophosphatemia with hyperphosphaturia (ARHR). Research in the Lanske Lab has provided important data regarding FGF-23, its relationship to other mineral homeostasis regulators such as PTH (parathyroid hormone), Klotho and vitamin D and how it functions in these disease processes. FGF-23 was also found to affect bone mineralization independent of its role in systemic phosphate homeostasis, adding significant new data regarding FGF-23’s physiological properties. The work in the lab continues to explore the complex interactions of FGF-23, PTH, vitamin D and other molecules using a new innovative mouse model for which Dr. Lanske received one of the few Challenge Grants from the National Institutes of Health.
More recently the Lanske Lab has expanded its research to investigate the role of Klotho during chronic kidney disease (CKD). Special emphasis is given to explore the possible role and source of Klotho in the development of metabolic bone disease (MBD - renal osteodystrophy). Furthermore, sophisticated in vivo techniques are being applied to identify the responsible genes and/or signaling pathways involved in the development of parathyroid gland hyperplasia during various diseases.
The Lanske Lab is also investigating how Indian hedgehog (Ihh), PTH-related protein (PTHrP) and other factors regulate the growth and maintenance of skeleton. These processes are controlled by a complex network of genes, and unraveling this network is critical to understanding and developing clinical responses for developmental defects, disease processes and skeletal regeneration. The work on Ihh has revealed crucial information on the roles of this and other key genes in the core regulatory mechanism of the development and maintenance of the growth plate and subsequently endochondral bone formation. Recent experiments have identified additional factors in this regulatory network which are now being included in the investigations.
Visiting assistant professor
Komaba Hirotaka, MD PhD
Junichi Hanai, MD
Postdoctoral research fellows
Tadatoshi Sato, PhD
Katsuhiko Amano, DDS, PhD
Noriko Ide, MD, PhD
Jovana Kaludjerovic, PhD
Michael Densmore, MA
Yi Fan, DMD
Elmisalati Waeil H, MMSc
Yefu Li , MD, PhD, Assistant Professor of Developmental Biology
Dr. Li has been a faculty in the Department of Developmental Biology at Harvard School of Dental Medicine and in the Faculty of Medicine at Harvard Medical School since 1999. He has been mentoring pre-doctoral students and post-doctoral fellows in his laboratory. Research projects in Dr. Li’s laboratory have been supported by the National Institutes of Health of the United States and Non-Federal foundations.
Fields of Interest
1) HTRA1-DDR2-MMP-13 Axis in Development of Osteoarthritis
Based upon the data from our investigations and others’ studies, we propose a molecular sequence of events underlying articular cartilage degeneration as follows: Excessive mechanical stresses (either by normal mechanical loading of defective joints or overloading of normal joints) can activate signaling pathways in chondrocytes, such as transforming growth factor beta 1 and Wnt/β-catenin pathways. This, in turn, induces expression of a serine protease, high temperature requirement A1 (HTRA1). Consequences of the induction of HTRA1 are degradation of the pericellular matrix of chondrocytes and enhanced exposure of chondrocytes to type II collagen. Interaction of chondrocytes with type II collagen results in enhanced signaling through a cell membrane receptor tyrosine kinase, discoidin domain receptor 2 (DDR2), which induces the expression of the matrix metalloproteinase 13 (MMP-13), as well as expression of DDR2 itself. MMP-13 degradation of type II collagen and aggrecan results in type II collagen and aggrecan fragments, which in turn may activate signals that further increase the synthesis of MMP-13. The result is a feedback amplification loop that causes irreversible articular cartilage degeneration. Currently, we are utilizing mouse genetic approaches to test this molecular sequence of the events in development of OA.
2) Genetic regulation of skeletogenesis
One of the interesting questions in the study of skeletogenesis is how chondrogenesis and osteogenesis are coordinated during endochondral bone development (hypertrophic cartilage replacement by bone). We have been addressing this question by utilizing a mouse mutant strain, osteochondrodystrophy (ocd). The ocd is a spontaneous mutation and homozygous, ocd/ocd, mice exhibit a short stature approximately 7 days after birth. Results from histology analysis demonstrated abnormality in growth plates of the mutant mice, such as disorganized proliferating chondrocyte columns, a reduction in numbers of proliferating chondrocytes, a small size of hypertrophic chondrocytes, a decrease in amount of trabecular bone. This suggests that ocd is a critical genetic factor regulating chondrogenesis and bone formation during the most active phase of skeletal growth. For understanding the nature of the ocd mutation, we established a high-resolution genetic linkage map of the ocd locus and obtained the physical map of the genomic interval including ocd. The interval contains about 1.1 million DNA base pairs. We found the mRNA level of one of the open-reading frames within the genomic interval was dramatically reduced, compared with that of the wild-type littermates. The cDNA and 2 kb up-stream DNA sequence of this open-reading frame was sequenced. No simple mutations, such as a point mutation, deletion and insertion, have been identified in the open-reading frame in ocd/ocd mice. We plan to continue our effort to identify the ocd mutation by direct DNA sequencing of the entire genomic interval of the ocd region.
Visiting Scholar: Dr. Tian Tang
Graduate Students: Dr. Michelle Mian
Dr. Lauren Manning
Dr. Rebecca Chen
Dr. Nithya Chickmagalur
Dr. Peter Chen
Malcolm R. Whitman , PhD, Professor of Developmental Biology
Our laboratory is interested in how cellular signals regulate biological responses to disease, damage, or stress within an organism, and how these same cellular signals effect the formation and movement of tissues within a developing embryo. A major lab focus is defining the molecular basis for the specificity of ligands of the TGFß superfamily during the processes of disease, tissue regeneration, and embryonic patterning. TGFßs are critical regulators of inflammation and autoimmunity, wound healing, muscle and bone maintenance, tumor cell behavior, and embryonic patterning. Many of these activities are important potential targets for pharmacotherapy. Our long-term goal is to establish the molecular basis for the specificity of clinically important responses to TGFß, making possible new approaches to disease therapy through signal inhibition.
Tracy Leigh Keller
Postdoctoral research fellows
Roland Baron , DDS, PhD, Chair and Professor of Oral Medicine, Infection, and Immunity; Professor of Internal Medicine, Harvard Medical School and Massachusetts General Hospital
The Baron laboratory focuses on signal transduction and the ways in which it controls cell differentiation and function. For this purpose, members of the lab study primarily skeletal development and remodeling as a model system. In this context, the program of the laboratory is divided in three well-defined but highly interactive main research goals:
1. Understanding the role of the AP1 family of transcription factors, specifically Delta FosB in skeletal development and in particular in the determination of mesenchymal cell lineages between the osteoblast and adipocyte cell types.
2. Characterizing the role of Src tyrosine kinase and its substrate Cbl in the signaling from integrins and other receptors involved in cell adhesion and migration, the role of ubiquitination in these processes, and the role of these processes in cell migration, using as a model system the migration and function of the bone resorbing cell, the osteoclast.
3. Characterizing the molecular mechanisms by which the G Protein-coupled calcitonin receptor regulates the cytoskeleton, adhesion and migration in osteoclasts, and its cross-talk with integrin signaling, Src, Cbl, and the focal adhesion kinase Pyk2.
Dr. Baron’s approach combines in-vitro and in-vivo experiments—often involving genetically modified transgenic or knockout mice and their isolated cells—that integrate molecular, cellular, and in-vivo studies to determine both the molecular mechanisms of cell biology and pathology and the impact of these mechanisms and their alteration at the organ level in normal and disease conditions. This work is directly relevant to several medical issues, including osteoporosis, bone metastasis in cancer, cancer itself through his focus on several proto-oncogenes, and endocrine disorders.