A bevy of new research grants for the Center for Musculoskeletal Research

Dr. David Guzick, M.D., Ph.D.

March 20, 2009

The Department of Orthopaedics is a very busy, highly clinical department. In its state-of-the-art, 100,000 sq ft comprehensive outpatient facility at Clinton Crossings, faculty members provide care for more than 160,000 orthopaedic outpatient visits yearly. There is now a planned expansion to satellite sites in the community. The 12,000 inpatient and outpatient operations performed annually by orthopaedic faculty members represent a two-fold increase over the past seven years. Moreover, Orthopaedics has expanded to include a major presence at Highland Hospital, where several key programs reside, including the Evarts Joint Replacement Center, Geriatric Fracture Center, and Musculoskeletal Oncology service.

There is another, very powerful, side to the Department of Orthopaedics, however. Through development of the Center for Musculoskeletal Research at SMD, which mainly includes faculty members in Orthopaedics but also houses faculty in Medicine, Pathology and Biomedical Engineering, the Department of Orthopaedics has been the number 1 NIH funded orthopaedics program since 2007.

Successful though they may be, Center faculty members have not rested on their laurels. Indeed, in the very last NIH grant cycle, 6 new R01s were awarded to faculty—with scores ranging in the 1st-5th percentile and the kind of laudatory reviews that make a Dean’s heart sing. Adding the 2.4 million dollars obtained in NYS Stem Cell funding and an NIH SBIR grant to a company started by one of the faculty, this is certainly an SMD record for new grants in a single grant cycle to a Department or Center, certainly in my 7-year experience.

This achievement is also a natural topic for a newsletter. Each field of research has its unique features that influence the level of success that can be achieved by a given scientific group. And we certainly have many successful research groups in all corners of the medical school. The recent success of faculty in the Center for Musculoskeletal Research, however, is particularly noteworthy.

This newsletter is divided into two sections. The main part is an overview of the history of the Department of Orthopaedics. While there will be some reference to the clinical component (how can it be ignored?), my emphasis will be on the evolution of its research program and its current practices in grant review and submission. Then, for those who are interested in learning more about the scientific projects that were funded and their Principal Investigators, the second part presents grant abstracts and biosketches.

The evolution of musculoskeletal research at the University of Rochester School of Medicine and Dentistry

Up until 1974, Orthopaedics was a Division of the Department of Surgery. In 1974, when Orthopaedics became a freestanding department, C. McCollister (Mac) Evarts, MD, an alumnus of SMD Class of 1957 and a graduate of our residency program, was recruited back from Cleveland Clinic as the Founding Chair.

Mac inherited a faculty of five, a clinic of four exam rooms, and small research laboratory. Dr. Richard Burton, who was also at the Cleveland Clinic, joined Dr. Evarts in moving to Rochester in the summer of 1974 to head up the Division of Surgery of the Hand, followed in early 1975 by Kenneth DeHaven, MD, to head up the Division of Sports Medicine. Having begun the first academic sports medicine division in the United States at the Cleveland Clinic, Dr. Evarts believed that it was natural to follow with the recruitment of Ken DeHaven to head that unit at the University of Rochester. The Department was able to raise sufficient philanthropic support to create the Clark Musculoskeletal Unit, which served the Department for many years until the Clinton Crossings Building was constructed. The original challenge was to grow the clinical enterprise in order to provide subsidization for the growth of the Department in research and education. Very early on, a PhD, John Brand, was recruited and this was followed by the recruitment of Ed Puzas. Both individuals were key to the current success in funded research in the Department of Orthopaedics. In 1987, Dr. Evarts was recruited to become Dean and CEO of the Penn State/Hershey Medical Center. He retired from that position in 2002, but returned to URMC in 2003 and was Medical Center CEO from 2003-2006. Coming full circle, Mac is now greatly enjoying his current role of Director of the Orthopaedics residency program.

A truly special feature of Orthopaedics, which has no doubt contributed to its success, is continuity of leadership. Richard Burton, MD, took up the reigns of the Department in 1987. Dr. Burton, who was recruited with Dr. Evarts from Cleveland Clinic in July, 1974, had a vision that the Department would excel in research, in education, and in all aspects of patient care with a balance of commitment to excellence in all three of these areas. Randy Rosier, MD, PhD was an Assistant Professor recruited by Dr. Evarts, and Dr. Puzas had just been appointed Associate Professor. John Brand, PhD, who headed research, left the Department for a position in industry early in 1987. Drs. Rosier and Puzas each had about $100K in annual funding from NIH.

Dr. Rosier was seriously considering leaving URMC because of no assigned OR time, doing most of his big operative procedures at night, and with an unpredictable schedule that hampered his research efforts. Dr. O’Keefe had just finished his PGY-1 in residency and had been hoping for a year in the lab, but there was no funding for the lab position, nor for his salary. In 1987, Dr. Burton put the following key building blocks in place for the Orthopaedics research program. First, he appointed Dr. Puzas as Associate Chair for Research. Ed recalls feeling that here was an opportunity to advance science for the benefit of clinical problems. The conversations around the "water cooler" between lab scientists and clinicians laid the foundation for creating one of the first translational research laboratories, decades before it became the goal of NIH and other foundations. He had ambitious goals for the Department – his vision was to achieve a top ranking in research funding, but even more important was the contribution he felt the research program could make to bettering the conditions of patients — and has since been successful well beyond his quite ambitious goals. Second, Dr. Rosier was given allocated OR time, thus stabilizing his schedule and making his lab efforts more realistic. Third, a funding stream for support of Dr. O’Keefe was created from departmental faculty clinical revenues, thus permitting Dr. O’Keefe to start the first of his two years in the research lab, between his PGY 1-2 years. After completing his residency at SMD and his oncology fellowship at Massachusetts General Hospital, Regis returned to Rochester, and completed his PhD in Biochemistry. Due to the rapid growth of his grant funding, and his clinical contributions to orthopaedic oncology and to the educational program, Dr. O’Keefe proceeded quickly through the academic ranks, reaching Professor with Tenure in 2007.

Seed money, taken from clinical revenues, provided for resident research projects, many of which (with Ed Puzas’ mentorship) resulted in external grant funding for these residents from the national-level Orthopaedic Research and Education Foundation. A grateful patient donor (Bob and Toni Gordon) provided $350,000 towards lab expansion. The Donald and Mary Clark Chair was established from a donor in 1994 for the head of research. Dr. Puzas was appointed to that Chair in that same year, and continues in that Chair to the present time. The Marjorie Strong Wehle Chair, to be held by the Department Chair was established in 1995.

The Gordon gift for research labs was supplemented by matching SMD funds to expand the research labs to about 2800 square feet, which was followed by major increases in NIH research funding for Drs. Puzas, Rosier, and O’Keefe. During this time, a model for Dr. Rosier and Dr. O’Keefe was established. Each alternated 4 months clinical and 4 months research, each with their own independent research practice, but sharing a single clinical practice. This resulted in the upward trajectory of the overall research effort, with the team of Drs. Puzas, Rosier, and O’Keefe, joined by Eddie Schwarz, PhD in 1998.

Dr. Burton stepped down from the Chair in 2000, handing the reigns to Randy Rosier, MD, PhD, a 1979 graduate of our MSTP program). By that time, because of the foundation laid by Drs. Evarts and Burton and their faculty, the department had become nationally recognized for the excellence of its clinical subspecialties and its developing research laboratory. However, he comments that the Department was a “victim of its own success” in that there was a critical shortage of space for any future growth of clinical or research programs. One of his top priorities was to obtain sufficient space and funding to create a Center for Musculoskeletal Research, in conjunction with plans that had been evolving for almost a decade to create an offsite Musculoskeletal Clinic to accommodate clinical growth. This clinical facility brought together not only Orthopaedic faculty, but faculty in Imaging Sciences, Rehabilitation, Rheumatology, support services, (e.g., physical, occupational, sports, and hand therapy). This was the first example of an offsite, “one-stop shopping” facility for a URMC service line.

In addition, during the first few years of Dr. Rosier’s leadership, there was renovation of 12,000 sq ft of laboratory space, allowing creation of the Center for Musculoskeletal Research. Randy expanded research faculty from 4 to 11, and also engaged a number of faculty from other departments into the Center. Over the next few years, SMD’s Department of Orthopaedics became the #1 NIH funded department nationally. Total research funding grew from about $1M annually to nearly $9M from 2000-2007. Many new multidisiciplinary research programs were developed due to the Center’s collaborative and translational approach, including a Program Project Grant (“Lead and Osteoporosis”, PI: Edward Puzas, PhD) a training grant (PI: Regis O’Keefe, MD, PhD), and a Center of Research Translation (CORT) award (“Translating Molecular Signal Pathways to Orthopaedic Trauma Care” PI: Randy, Rosier, MD, PhD). In addition, the Department was able to nearly double its endowment to help provide stability and support of its academic programs.

In 2007, Dr. Rosier decided to step down as Chair in order to focus on his CORT Center and other research activities. Regis O’Keefe, MD, PhD was appointed as Chair. This was, for myself and Dr. Berk, a straightforward decision in view of Regis’s accomplishments and leadership skills, and also in view of the fact that he had been recruited to be Chair of several of the most prestigious departments in the nation. Since his appointment, in addition to managing the oft-challenging clinical affairs of the Department, Dr. O’Keefe has driven the research effort of the Center even further, emphasizing… emphasizing the development of collaborative research teams, a strong mentoring program, and a translational research program built upon a solid foundation of high quality basic research. The department has furthermore developed a clinical research core facility and clinical faculty member are enrolling patients in more that 70 open clinical trials.

Of particular note, Dr. O’Keefe believes that the Center’s research lab meetings have been instrumental in their success. This meeting takes place each Friday morning and all PIs participate. Typically 10-12 PIs are present, many of whom have significant grant writing experience and review experience. Drs. Brendan Boyce, Laura Calvi, and Di Chen are currently members of study sections. Drs. Ed Puzas, Randy Rosier, Regis O’Keefe, and Eddie Schwarz have served on study sections. Dr. O’Keefe was a prior chair of the Skeletal Biology and Skeletal Regeneration study section. Dr. Rosier was a member of the NIH Council. At the meeting, PIs that will be submitting grants present specific aims, preliminary data, and key components of their experimental design. The meeting is highly interactive. The PI takes the suggestions and returns with a revised application for presentation 3-4 weeks later. In addition, members of the Center are encouraged to seek the input of other members of the Center during the writing process. This culture of collaboration in the process has enabled construction of well thought out grants with feasible approaches aimed at important scientific questions.

In addition, the members of the Center also participate in two additional joint laboratory meetings. On Tuesday morning 3 post-doctoral fellows and/or graduate students present their most recent (6-8 week) data to all Center meetings. These 20 minute presentations are highly interactive and serve as an important mechanism to mentor both the student and the PI alike. Additionally, these sessions have served to develop collaborations, since PIs or others in the audience frequently have suggestions about directions or models that can be applied to the research area under discussion. On Wednesday mornings, two post-doctoral fellows and/or graduate students provide 30 minute presentations to all Center members. These are more formal presentations and provide a summary of the work, including the manner in which the findings address important hypothesis and potentially alter or extend paradigms for a given disease process.

While these activities require substantial investment of time, the interactions promote a rich intellectual environment for each investigator and trainee. Indeed, during the last funding cycle, the payoff was substantial, as evidenced by the grants listed below:

Upon his return to Rochester in 2003, and continuing since that time, Dr. Evarts has truly enjoyed watching his baby grow to maturity. He comments that “the changes that have occurred in Orthopaedics are no less than stunning. The Clinton Crossings Building has served as a beacon for expeditious delivery of superb clinical care. The Musculoskeletal Research Institute has grown to be the number one funded department in the United States. The faculty growth has been no less than phenomenal with critical mass in all ten Divisions of Orthopaedics. The residents have grown from two to six per year, with one research fellow, and there have been fellowships created in Hand, Sports, Spine, Foot, Ankle, and Trauma. From very modest beginnings, there has been an incredible explosion of a department that I believe is superbly balanced between research, education, and patient care.”

Recent Grants Awards

PI: Hani Awad NIH/NIAMS 1R01AR056696-01A1 “Allografts and Gene Therapy in Flexor Tendon Tissue Engineering”
This project pursues a clinically-translational paradigm in tissue engineering of flexor tendons, whose injuries are frequently associated with debilitating adhesions. After developing the first mouse model of flexor tendoplasty, we identified that the Growth and Differentiation Factor 5 (GDF-5) has anti-scarring effects. Using models of loss and gain of function, we are now investigating the underlying mechanism of the observed GDF-5 effects. We are also exploring the use of the clinically-acceptable biological allograft as an acellular scaffold for drug delivery. Our approach epitomizes interdisciplinary research as it involves engineering, molecular biology, gene therapy, and biomaterial processing concepts, and has broader applicability to other soft musculoskeletal tissues such as cartilage, meniscus, and intervertebral disc.

PI: Hani Awad NYSTEM N08G-019 “Modulating Stem Cell Differentiation using Novel Allograft Scaffolds for Cartilage Repair”
We recently developed novel porous scaffolds derived from freeze-dried cartilage allograft tissue and demonstrated that these scaffolds can be efficiently seeded with stromal mesenchymal stem cells (MSCs) for cartilage tissue engineering. The scaffolds have several empirical advantages over man-made biomaterials (synthetic or biological) the most important of which is their content of native growth factors (e.g. cartilage-derived morphogenetic proteins or CDMPs) and native extracellular matrix molecules that provide crucial signals to regulate the differentiation of the MSCs into functional hyaline cartilage. The project aims to characterize and optimize the physicochemical composition of the porous cartilage scaffold and to evaluate the efficacy of implanting MSC-seeded porous cartilage scaffolds to repair focal articular cartilage defects in a preclinical in vivo model.

PI: Laura Calvi, MD NIH/NIDDK DK081843-01A1 “Regulatory cell interactions in the bone marrow”
The long-term objective of this proposal is to define the cellular and molecular mediators crucial for osteoblastic control of hematopoietic stem cells (HSCs). We have established that parathyroid hormone (PTH) activates osteoblastic cells to increase HSC numbers and that PTH improves HSC survival after radiation injury. These results suggest a novel therapeutic approach to increase HSCs by stimulating osteoblastic cells. However, the specific osteoblastic subsets and the key molecular events involved are unknown. Using pharmacologic and genetic models, we have identified Notch signaling as a potential mediator of PTH-dependent HSC regulation. Notch activation requires direct interaction of cell-bound ligands with receptors on neighboring cells. We demonstrated that 1) PTH or activation of its receptor (PTH1R) stimulate the Notch ligand Jagged1 (Jag1) in osteoblastic cells; 2) in mice with constitutively active PTH receptors in osteoblastic cells, HSCs have increased Notch activation; 3) the PTH-dependent HSC increase is blocked by inhibition of γ-secretase activity, which is required for Notch activation. Our preliminary studies now demonstrate that expression of Jag1 in osteoblastic cells is required for the PTH-dependent HSC expansion. Together, these data suggest that PTH expands HSC through osteoblastic expression of Jag1, which then activates Notch signaling in neighboring bone marrow cells. Based on our data, we hypothesize that HSC expansion by osteoblasts requires Jag1-initiated Notch activation in the bone marrow microenvironment. To test this hypothesis, we propose the following specific aims: 1. To define the osteoblastic niche cells in which Jag1 is necessary and sufficient to mediate HSC expansion using specific genetic models of lack or overexpression of osteoblastic Jagged1; 2. To identify the cell population (HSC, osteoblastic cells and/or other components of the bone marrow) in which Notch activation is required to achieve osteoblastic-dependent HSC expansion using targeted genetic models in which Notch signaling cannot be activated; 3. To determine the contribution of Notch signaling to the myeloprotective effects of PTH using the animal models defined above. We have already established and fully characterized in vivo models in which microenvironmental signals increase HSCs. Now that osteoblastic Jag1 has been identified as a key element of PTH-dependent HSC expansion, we have the unprecedented opportunity of defining the cellular and molecular components of the HSC niche using the in vivo strategies proposed here. Completion of our experimental aims will thus define novel therapeutic targets for HSC manipulation in the bone marrow microenvironment, which can be exploited to improve survival after bone marrow injury.

PI: Laura Calvi, MD NYSTEM N08G-322 “Therapeutic stimulation of the hematopoietic stem cell niche”
Hematopoietic cell depletion after chemotherapy and radiation causes morbidity, mortality and prolonged hospitalization in cancer patients and after environmental toxins or radiation exposure. Strategies to accelerate hematopoietic recovery could avoid pancytopenia and dramatically improve host response to infections. Recently we have identified pharmacologic strategies that specifically target and expand subsets of the hematopoietic stem cell pool. However, which of these strategies is superior in the setting of myeloablation, and which cellular and molecular mechanisms are involved is unknown. The studies proposed in this grant utilize in vivo models to determine if manipulation of specific hematopoietic stem cells in the bone arrow through microenvironmental stimulation accelerates full hematopoietic recovery. Selective HSC expansion through niche activation could revolutionize the management of patients with cancer and myeloablative injury.

PI: Di Chen, MD, PhD NIH/NIAMS AR055915-01A2 “β-Catenin Signaling and Pathogenesis of Osteoarthritis”
Osteoarthritis (OA) is a degenerative joint disease and the mechanism of this disease is poorly understood. The articular chondrocyte is the only cell type in articular cartilage and these cells are responsible for maintaining the appropriate structure and function of the articular cartilage tissue. The function of articular chondrocytes is regulated by a variety of growth factors, including Wnt family members. Recent human genetic studies demonstrate that patients with a mutation in the secreted frizzled-related protein 3 (sFRP3), a Wnt signaling inhibitor, have a predisposition for the development of OA. The underlying hypotheses of the current project are that 1) canonical Wnt/β-catenin signaling plays a key role and is required for sensing changes in meniscus injury and mechanical injury in articular chondrocytes and its abnormal activation will lead to the development of an OA-like phenotype; and 2) Bmp2 and Mmp13 are key downstream target genes of β-catenin signaling in articular chondrocytes and deletion of these genes will significantly reverse the OA-like phenotype observed in β-catenin conditional activation mice. In Aim 1, we will analyze β-catenin conditional activation mice and determine the age-dependent OA-like phenotype in adult β-catenin conditional activation mice. In Aim 2, we will determine the role of meniscus injury or mechanical injury in activation of β-catenin signaling and the development of OA. In Aim 3, we will determine if Bmp2 and Mmp-13 are key downstream mediators of β-catenin signaling during the development of OA in adult β-catenin conditional activation mice. Our proposed studies will provide novel and definitive evidence about the role of β-catenin signaling in articular chondrocyte function and OA pathogenesis.

PI: Di Chen, MD, PhD NYSTEM N08G-070 New York State Department of Health and the Empire State Stem Cell Board “Canonical Wnt Singaling Controls Mesenchymal Stem Cell Differentiation”
Mesenchymal stem cells in bone tissue have the capacity to differentiate into different cell lineages, including osteoblasts, chondrocytes and adipocytes; they also interact with other cells in the bone marrow microenvironment, such as hematopoietic cells, to regulate their functions. The function of β-catenin in mesenchymal stem cell differentiation in postnatal and adult mice remains poorly understood. Using the newly developed approaches to generate mice with inducible conditional activation and conditional knockout of genes, we have discovered that β-catenin plays a key role in controlling mesenchymal stem cell differentiation into osteoblasts and adipocytes in postnatal mice. We also found that β-catenin regulates the interaction of mesenchymal stem cells with osteoclast precursors and modulates osteoclast formation in postnatal mice. The studies proposed in this application may help us identify a novel molecular target for the development of drugs for the treatment of osteoporosis and other metabolic bone diseases. Our future plans include determining why β-catenin signaling becomes defective with age and to develop strategies to genetically manipulate mesenchymal stem cells to differentiate into osteoblasts rather than adipocytes and to deliver them to bone.

PI: Regis O’Keefe, MD, PhD; Co-PI: Xinping Zhang, MD, PhD R01AR048681-06A1 NIH/NIAMS “Cyclooxygenases in Skeletal Repair”
The focus of the grant is on the role of COX-2 in fracture repair. In the first funding period we identified COX-2 as a signal important in the activation of stem cells in the bone injury environment. The grant renewal builds upon this initial funding period by showing that this important signal is perturbed during the aging process. Preliminary work for the grant showed that COX-2 is produced in the periosteal stem cells that line the bone surface following injury. The stem cells in children have a markedly increased potential for healing, compared to stem cells from older patients. We have recently shown that the periosteal stem cells in aged animals have reduced COX-2 expression and that this decrease is involved in their decreased bone healing potential. The experiments in the grant proposal use a series of in vitro and in vivo approaches to further define the signals and mechanism involved in the reduced COX-2 expression involved with aging. The work uses knock out mice and conditional knock out mice of the four PGE2 receptor subtypes. The identification of specific signals involved in the process increases the potential to develop important new therapeutic approaches.

PI: Edward M. Schwarz, PhD DE019902-01 NIH/NIDCR “PTH Effects of Craniofacial Allografts”
As a result of birth defects, trauma or cancer, there is a great clinical need for a tissue engineering solution to fill large bone voids in the head, which cannot heal on their own. Although cadaver bones (allografts) have been used to fill these defects, they elicited a host inflammatory response that leads to scar formation limiting their utility. Based on the remarkable success of recombinant parathyroid hormone (PTH, ForteoTM) therapy as a bone building agent in osteoporosis patients, pilot studies were performed to see this drug’s effects in mouse models of allograft healing. In addition to its remarkable effects on bone formation around the allografts, the results demonstrated complete inhibition of the inflammatory response and closely resembled scarless healing of live bone grafts. The goal of this new grant is to understand the mechanism by which PTH therapy mediates scarless healing of allografts, and translate this information into a novel tissue-engineering approach to treat patients with large segmental bone defects.

PI: Edward M. Schwarz AR056702-A1 NIH/NIAMS “B cells and draining lymph node function in arthritic flare”
Although there has been tremendous advances in our ability to treat patients with rheumatoid arthritis (RA), which represent 1% of our total population, the unmet needs remain great and effective therapies such as TNF inhibition and B-cell depletion therapy are highly immunosuppressive. Moreover, the interaction between TNF and B-cells in RA, as well as the mechanism of arthritic flare remain unknown. To adress these questions, we developed contrast enhanced (CE) MRI to study the natural history of disease in the TNF-transgenic (TNF-Tg) mouse model of RA. The surprising results demonstrated that dramatic changes in B-cell populations within draining lymph-nodes correlate with inflammation and focal bone errosion in the afferent joint. Furthermore, effective anti-TNF and B-cell depletion therapy correlates with reversion of the pathologic lymph-node changes. Subsequently, we have made similar observations in RA patients, which warrant further investigation. Thus, the goals of this new grant are: 1) to formally establish the cause-effect relationship between B-cell changes in draining lymph nodes and arthritic flare; 2) to evaluate a novel anti-CXCL13 treatment that would prevent the B-cell changes without immunosuppression; and 3) investigate the translational potential of this program by imaging affected lymph nodes of RA patients before and after anti-TNF and B cell depletion therapy.

PI: Edward M. Schwarz R43 AR057589-01 NIH/NIAMS “Laser-guided gene therapy for cartilage defects”
Recent progress in musculoskeletal research has greatly benefited from the advances in molecular biology uncovering the role of specific genes in osteoarthritis (OA). In this gene-centered paradigm, OA pathogenesis results from the lack of appropriate gene expression follow cartilage injury. Therefore inducing the expression of desirable genes is critical. Unfortunately, the absence of a safe and effective gene delivery system has prohibited this approach of gene therapy for articular cartilage repair. LAGeT Inc. has developed a proprietary technology that aims for safe and efficient delivery and activation of a gene of interest in a site-specific manner. This technology, termed light-activated gene transduction (LAGT), works by irradiating the target tissue with long wave ultraviolet light (UVA) from a laser, rendering the cells susceptible to gene expression from a recombinant adeno-associated virus (rAAV). In this way, infection of laser-irradiated cells leads to efficient gene therapy, while non-irradiated bystander cells are unaffected. The goal of this phase 1 small business innovation research grant is to complete a series of proof-of-principle studies that will define LAGT’s safety and efficacy to repair articular cartilage defects from sports related injuries.

PI: Xinping Zhang, MD., PhD NYSTEM N08G-495 “Gli2 Activated MSCs for Bone Regeneration and Reconstruction”
Adult mesenchymal stem cells (MSCs) have enormous potential for bone tissue regeneration. MSCs can be readily isolated from various tissues and are considered to be the most important building block for bone tissue regeneration. Work in our laboratory has led us to embark on an endeavor that aims at engineering of a tissue replacement mimicking the potent regeneration capacity of periosteum. Periosteum is a well-vascularized tissue that covers the outer surface of the bone. Periosteum contains a large number of MSCs that can form bone at the time of injury. Our plan is to assemble a tissue construct containing biodegradable scaffold, MSCs and genes that can induce bone formation at the site of compromised periosteum. The key to the success of the approach is to identify adequate MSCs and critical genes that direct the MSCs to form bone at the site of injury. To this end, we isolated MSCs from periosteal tissue at the site of injury and further identified a gene, known as Gli2, which can effectively drive periosteal MSCs to form excessive bone in an animal model. These findings lay the foundation for our current application in which we will use cell culture models and a murine femur animal bone defect model to determine the effects of combining MSCs and Gli2 gene in regeneration of a functional tissue replacement for repair of bone defects.

Biosketches

Hani Awad, PhD is currently an Assistant Professor in the Departments of Biomedical Engineering and Orthopaedics and a principal investigator in the Center for Musculoskeletal Research. He received his PhD degree in 1999 at the University of Cincinnati and later completed a post-doctoral fellowship at Duke University. Since joining the University of Rochester in the Fall of 2004, Dr. Awad has developed new and independent and collaborative research programs focusing on musculoskeletal tissue engineering, won several grant awards from the NIH and multiple foundations, and authored 21 peer-reviewed manuscripts out of a total of 41 published papers to date. Dr. Awad has received multiple honors including the Wallace H. Coulter Foundation Early Career Translational Research Award in Biomedical Engineering. In addition, Dr. Awad along with the research group from his alma mater won the 2007 Kappa Delta Ann Doner Vaughn Award in recognition of their research on Functional Tissue Engineering for Tendon Repair. This award is the highest research award given by the American Academy of Orthopaedic Surgeons (AAOS) and the Orthopaedic Research Society (ORS), and places him among an elite company of previous award recipients.

Laura M Calvi, MD is an Associate Professor of Medicine in the Center for Musculoskeletal Research. She received her degree in Biology summa cum laude from Union College NY (1990) and her medical degree at Harvard Medical School (1995). She trained in Internal Medicine and Endocrinology at Massachusetts General Hospital, where she completed her post-doctoral work in Hank Kronenberg’s laboratory studying the action of Parathyroid hormone on bone biology. Her research interests are focused on the role of the bone marrow microenvironment in hematopoietic stem cell regulation, including: 1) molecular mechanisms of osteoblastic activation of hematopoietic stem cells, 2) role of other bone marrow cellular components (osteoclasts, endothelia cells and adipocytes) in hematopoietic regulation, 3) effects of malignancy on the normal hematopoietic stem cell niche and 4) regulation of malignant stem cells by microenvironmental factors. She is a member of the American Society for Bone and Mineral Research (ASBMR), the Endocrine Society and the American Society for Hematology (ASH). She is currently a member of the ASBMR education committee (2006-2009). She received several awards, including the ASBMR Young Investigator Award and the Pew Scholar in Biomedical Science. She is the program director of the Endocrinology and Metabolism Fellowship Program at the University of Rochester. She joined the Division of Endocrinology at the University of Rochester in August, 2002 from the Endocrine Unit at Massachusetts General Hospital.

Chen Di Chen, PhD is Professor of Orthopaedics in the Center for Musculoskeletal Research at the University of Rochester. He received his medical degree (1982) at Tianjin Medical University, China and his PhD degree (1992) at University of Louisville (1992). His research is supported by several NIH grants and he has published 61 original articles, 13 review articles, 12 book chapters and 6 US and international patents. His research interests are focused on bone development and remodeling, including: 1) pathological mechanisms of osteoporosis and osteoarthritis, 2) genetic mouse models specifically targeting osteoblasts and chondrocytes, 3) osteoblast and chondrocyte biology, and 4) bone cell BMP and Wnt signaling, protein ubiquitination and sumoylation, and micro-RNA regulation. He is member of ASBMR, IBMS, ORS, and NYAS. He is also a member of ASBMR education committee (2007-2010) and a co-chair of ORS Bone Sub-Topic committee (2007-2010). He has received several awards, including the Novartis Young Investigator Award and an NIH Independent Scientist Award. He is a regular member of a NIDCR Special Grant Review Committee and editorial board members for the Journal of Bone and Mineral Research, Journal of Cellular Biochemistry, Calcified Tissue International, and Journal of Orthopaedic Surgery and Research.

Regis O’Keefe, MD, PhD is the Marjorie Strong Wehle Professor and Chair, Department of Orthopaedics. He is also the Director of the Center for Musculoskeletal Research. Dr. O’Keefe earned his BA magna cum laude at Yale in philosophy and religious studies. After earning his medical degree from Harvard Medical School in Boston, Massachusetts, he completed a Ph.D. in Biochemistry and Biophysics from URSMD. Dr. O’Keefe served his internship in surgery at New England Deaconess Hospital in Boston, his residency in orthopaedics at the University of Rochester Medical Center and an oncology fellowship at the Massachusetts General Hospital. In 1993, he joined the faculty at the University of Rochester. Dr. O’Keefe has authored or coauthored over 200 articles, more than 300 abstracts, 14 book chapters and reviews concerning bone repair and development, cancer, inflammatory diseases of bone, genetics, and related topics. Most of his primary research has been supported by NIH grants, and his NIH funding has consistently placed him among the most highly funded orthopaedic surgeon-clinician scientists in the United States. Dr. O’Keefe is an associate editor of the Journal of Bone and Mineral Research. Dr. O’Keefe has served in many leadership roles with a number of national orthopaedic organization including: American Academy of Orthopaedic Surgeons (“AAOS”) and is on the Board of Directors of the Orthopaedic Research Education Foundation (“OREF”) and American Board of Orthopaedic Surgery (“ABOS”) and currently is the President of the Orthopaedic Research Society (“ORS”).

Edward Schwarz, PhD is currently Professor in the Department of Orthopaedics and the Associate Director of Center for Musculoskeletal Research at SMD. He received his PhD degree in Microbiology & Immunology from the Albert Einstein College of Medicine, New York, NY (1993), and completed his Postdoctoral Fellowship at the Salk Institute, La Jolla, CA (1997), before joining the faculty of Division of Allergy, Immunology & Rheumatology in SMD’s Department of Medicine. His research interests are focused on pathologic conditions of inflammatory bone loss (rheumatoid arthritis, bone infections, tumor metastases and periprosthetic osteolysis), and also tissue engineering of musculoskeletal tissues including bone, cartilage, ligament and tendon. He has received several awards, including Fellowships from the Arthritis Foundation & National Multiple Sclerosis Society, the ORS Harris Award and the AAOS Kappa Delta. He has served on various NIH Study Sections, Chaired the Orthopaedic Research and Education Foundation Basic Science Study Section, and served as an editorial board member for the Arthritis Research & Therapy and Arthritis & Rheumatism. His research has been supported by 18 NIH grants, several foundations, industry, and the DoD. He has published 161 original articles and 8 book chapters. He is a named inventor on 5 US and international patents. In 2001 he founded LAGeT Inc. based on his laser-guided gene therapy technology, and serves as the company’s President.

Xinping Zhang, MD, PhD is Assistant Professor of Orthopaedics in the Center for Musculoskeletal Research. She received her MD degree (1990) from Shanghai Medical University in China (year) and her PhD degree (1998) in Biochemistry from UR SMD. She joined the Department of Orthopaedics in 1999 and completed her postdoctoral training in 2002. Her research interests have been focused on mechanisms of skeletal healing, which integrates the following topics: 1) the role of mesenchymal stem cells in injured bone microenvironment; 2) signals and signaling pathways essential for mesenchymal stem cell differentiation, and 3) stem cell therapy and tissue engineering of periosteum for improved osseointegration at cortical bone junction. She has received several awards, including ORS Young Investigator Award, Travel Fellowship Awards and J.R. Neff Award from MTF. Her research is supported by NIH, MTF, OREF and the UR CTSA.

Meliora,

David S. Guzick, MD, PhD
Dean, School of Medicine and Dentistry
University of Rochester

Dean's Newsletter

Posted May 28, 2009:
A Fond Farewell to the University of Rochester

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