Cellular & Molecular Biology:
Nicholas U. Ahn, MD, Assistant Professor
Research Interests:
Dr. Ahn’s current research is geared both towards clinical and basic science studies. His primary basic science focus is on disk degeneration and mechanisms to reverse the degenerative process.
His studies on rabbit disk metabolism demonstrated that decreased nutrition is a primary component in disk cell death. His clinical research has focused on risk factors for spinal degenerative disorders and on clinical outcomes after spinal surgery.
He performed a prospective 52-year study which demonstrated that smoking, hypertension, and hyperlipidemia are risk factors in low back pain and lumbar spondylosis. This suggested that the vascular hypothesis of low back pain is valid and that diminished blood supply to lumbar disks is a causative factor in lumbar degeneration.
Also, his post-operative outcomes studies demonstrated that current techniques for treatment of back pain have low success rates. This has outlined the need for new, biologic solutions for this problem which relates to the basic science aspect of his research.
Finally, he is currently involved with the development of a clinical database at Case to facilitate clinical research with a focus on outcomes of surgical and non-surgical treatments for different musculoskeletal disorders.
Eben Alsberg, PhD, Assistant Professor
Research Interests:
Biomimetic tissue engineering; innovative biomaterials and drug delivery vehicles for functional tissue regeneration and cancer therapy; control of stem cell differentiation; mechanotransduction and the influence of mechanics on cell and tissue function; cell-cell interactions.
Dr. Alsberg’s laboratory focuses on engineering functional biologic replacements to repair damaged or diseased tissues in the body. We use the complex signals that are implicated in tissue morphogenesis, repair, and homeostasis as a template for the development of innovative biomaterials for tissue regeneration.
Through the precise temporal and spatial presentation of soluble bioactive factors, mechanical forces, and biomaterial physical and biochemical properties, we aspire to create microenvironments that regulate cell gene expression and new tissue formation.
Some areas of active investigation include controlling stem cell differentiation, delivering bioactive factors sequentially, developing spatially patterned constructs, understanding cell-cell interactions, and determining mechanical influences on cell function.
E-mail: eben.alsberg@case.edu
James E. Dennis, PhD, Assistant Professor
Research Interests:
Dr. Dennis's laboratory is currently focused on the area of tissue engineering as it relates to cartilage and bone repair.
One project looks at how different sources of cartilage cells can be used to generate repair cartilage with specific biomechanical properties and how that material can be used to repair trachea. A similar project using culture-expanded chondrocytes seeks to advance this technology for the repair of articular cartilage.
Both studies include the use of tissue culture techniques, including bioreactors, and analytical techniques such as biomechanical testing, imaging of cartilage constructs by high-resolution MRI, biochemical analysis of cellular and matrix components, and animal model testing.
Another major area is focused on the precise delivery of stem cells to selected targets via a transient coating of the stem cells with biomolecules that bind the target site. These targeting studies are directed at the local delivery of chondrocytes to repair cartilage and at the systemic delivery of osteogenic cells to bone marrow.
Another study, conducted in collaboration with Aastrom Biosciences Inc. and funded through NIH, deals with the optimization of the expansion of osteogenic progenitor cells and their use in bone repair. As part of this study, cell surface markers are being studied to determine which markers correlate with osteogenic potential, and how these markers can be used for dosing in a clinical setting.
The long-term goal of these studies is to produce osteogenic cells to repair clinical non-unions, and these studies have been used as a basis for FDA-approved clinical trials.
E-mail: james.dennis@case.edu
Reuben Gobezie, MD, Assistant Professor
Research Interests:
Dr. Gobezie's research uses a systems biology approach to studying musculoskeletal disorders with a focus on mass spectrometry, protein microarrays, and other proteomics techniques as well as bioinformatics.
The two major areas of research in his lab focus on arthritis and fracture healing. Specifically, Dr. Gobezie's group has identified the first highly predictive protein biomarkers for osteoarthritis (OA) by studying differential protein expression in synovial fluid from early and late OA against samples from healthy donors.
His group is now validating the tissue and disease-specific performance of these biomarkers in synovial fluid, blood, and urine from patients with rheumatoid arthritis. His laboratory is also studying the proteome of fracture healing, joint replacement failures, and rotator cuff disease.
Victor M. Goldberg, MD, Professor
Research Interests:
Cartilage metabolism, bone transplantation, models of osteoarthritis and rheumatoid arthritis, and biomechanics of joints and joint replacement.
Dr. Goldberg’s basic research includes investigations in bone and cartilage transplantation, new approaches to bone repair, and the exploration of new generations of prosthetic knee and hip joints.
Dr. Goldberg’s laboratory is investigating the approaches to the use of cellular-based technology in the repair of full- and partial-thickness articular cartilage defects. Studies have included investigations of bone and cartilage transplants with focus on experimental models evaluating the interplay of vascularization and immune response of the host.
These projects are closely related to other projects by faculty involving matrix molecular biology and cartilage repair technologies. The basic concept continues to be the use of novel cellular constructs using mesenchymal stem cells as the basis for the repair of full- and partial- thickness defects of articular cartilage.
New materials and interfaces are being explored with other investigators to develop new generations of prosthetic knee and hip joints, with the ultimate aim of optimal design and interface characteristics.
Edward M. Greenfield, PhD, Professor and Director of Research
Research Interests:
Our research focuses on cellular mechanisms that regulate bone turnover in response to stimuli such as hormones, cytokines, orthopaedic wear particles, and bacterial endotoxin. We study signal transduction, regulation of gene expression, and differentiation of bone cells (osteoclasts and osteoblasts).
These studies use cell cultures as well as in vivo mouse models. The roles of specific molecules are studied using a variety of techniques, including gene knock out, gene knock down (siRNA and antisense), and neutralizing antibodies.
These studies have important implications for the regulation of bone turnover in various diseases, including osteoporosis, loosening of orthopaedic implants, and tumors. Specific areas of current research include: the role of bacteria in "aseptic loosening" of orthopaedic implants, regulation of parathyroid hormone signaling by Protein Kinase Inhibitor (gamma), regulation of bone turnover by the gp130 family of cytokines, and novel tumor supressors/oncogenes in bone tumors.
Community of Science Profile:
E-mail: emg3@po.cwru.edu
Thomas M. Hering, PhD, Associate Professor
Research Interests:
Molecular biology of extracellular matrix in articular cartilage.
One project in Dr. Hering’s lab concerns transcription factors (zinc-finger proteins) that may regulate the differentiation of bone marrow-derived mesenchymal stem cells to chondrocytes. A zinc finger protein designated ZNF470, and the related protein in the mouse (Zfp28), are likely repressors of chondrocyte-specific gene expression.
The role of these regulators in chondrocyte differentiation is being studied using a variety of approaches, including overexpression in chondrogenic cell lines, chromatin immunoprecipitation and promoter microarray analysis to identify target genes, and the development of a conditional knockout mouse.
This work may lead to the development of therapies to enhance chondrogenesis during fracture healing and cartilage repair. A second project utilizes recombinant technology to produce wild-type and mutant recombinant aggrecan. Core protein sites are mutagenized to probe mechanisms for interaction between aggrecan and specific ADAMTS enzymes, a family of degradative proteases.
Ultimately, we are hoping to achieve a better understanding of the mechanism for regulating normal turnover of this structural component of cartilage, and for intervening in the accelerated degradative process that occurs in osteoarthritic cartilage.
Community of Science Profile
E-mail: tmh@po.cwru.edu
Shunichi Murakami , MD , PhD, Assistant Professor
Research Interests:
Molecular genetics of bone and cartilage. Signaling pathways that regulate chondrocyte and osteoblast differentiation.
Dr. Murakami’s laboratory focuses on the role of fibroblast growth factor (FGF) and mitogen-activated protein kinase (MAPK) signaling in mesenchymal cells. During embryonic development, FGFR2 is expressed in the perichondrium and periosteum in the long bones, mesenchymal cells in the cranial sutures, and osteoblasts.
Activating mutations in FGFR2 cause skeletal syndromes characterized by craniosynostosis. These include Apert and Crouzon syndromes. In contrast, FGFR3 is expressed in proliferating and prehypertrophic chondrocytes in the growth plates.
Activating mutations in FGFR3 cause the most common forms of human dwarfism, achondroplasia and thanatophoric dysplasias, indicating FGFR3 is a negative regulator of bone growth. We hypothesize that the MAPK pathway plays an important role in FGFR2 and FGFR3 signaling during skeletal development.
Dr. Murakami uses genetically engineered mice to identify the role of MAPK and FGFR in skeletal development. His recent genetic experiments strongly suggested that Fgfr3 signaling inhibits bone growth by inhibiting hypertrophic chondrocyte differentiation through the MAPK pathway.
Recent experiments also indicated that Fgfr3 and the MAPK pathway control the timing of growth plate closure. Dr. Murakami’s current research focuses on the mechanisms whereby Fgfr3 and the MAPK pathway control chondrocyte differentiation and closure of the growth plates.
E-mail: shun@case.edu
Guang Zhou, PhD, Assistant Professor
Research Interests:
Transcriptional control of bone and cartilage formation.
Dr. Zhou's laboratory focuses on studying how transcription factors interact with each other to determine cell fate and regulate cell function during skeletogenesis and bone metastasis.
Utilizing molecular, biochemical and genetic approaches, Dr. Zhou has shown that chondrogenic transcription factor SOX9 is a strong inhibitor for osteogenic transcription factor RUNX2 during bone formation. His laboratory is currently studying the role of SOX9 during chondrocyte hypertrophy using transgenic mice models.
Other projects include studying the roles of transcription co-factor Ctbp and tumor suppressor gene Rb in chondrocyte and osteoblast differentiation using transgenic and knockout mice models. His work will provide a better understanding of how tissue-specific and ubiquitous transcription factors interact with each other to control bone and cartilage formation.Eventually it could lead to the development of therapeutic and diagnostic methods for bone diseases.
E-mail: guang.zhou@case.edu