My interests have always centered on disorders that affect the human skeletal system. Common diseases such as osteoarthritis and osteoporosis cause significant disability in humans. These diseases are also costly to society. In the United States, more than 50,000 people annually undergo joint replacement surgery for hip osteoarthritis and more than 200,000 people annually suffer hip fractures due to osteoporosis. Many of my family members, friends, and colleagues have osteoarthritis or osteoporosis, and as I have gotten older, I've begun to develop many symptoms myself. Although these common, and now personal, diseases have had great impact on the direction of my research, an even greater impact has come from my clinical work with patients and their families who are affected by uncommon skeletal diseases. These diseases are individually rare, but in aggregate they account for a significant fraction of disability in children and young adults.
My laboratory's research into the growth and maintenance of the skeletal system begins with these patients. Through their generous participation in the research process we learn about the basic biologic processes that are essential to skeletal homeostasis and try to apply what we learn to improve the diagnosis, treatment, and prevention of all human skeletal disease. Since I am a geneticist and a pediatrician, many of the diseases that my lab studies are hereditary and affect children. We hypothesize that although the underlying etiologies for these rare disorders will differ from those of osteoarthritis and osteoporosis (i.e., genetic versus age related, acquired, environmental, or multifactorial), they will still identify biologic pathways that are important in many forms of bone and joint disease. Identifying the genes that cause rare skeletal diseases will give us access to pathways that present new targets of pharmacologic and other therapeutic interventions for all skeletal disorders.
Our approach to the study of human skeletal disease has some unique advantages. First, by beginning with a genetic disease, the pathway that we discover must be important, since genetic variation a priori causes disease. Even the rarest genetic disease can be studied because of the large size of the human population and the ability to establish international collaborations. These collaborations foster not only scientific research but also beneficial communications between clinicians, patients, and families. The willingness of patients from around the world to participate in research also makes it likely that a series of disease-causing mutations within a gene will be identified, allowing us to gain insights about protein structure and function that could not easily be derived from studying a single mutation. Finally, it is personally satisfying to design research that is intended to affect patients and their families positively and directly. In this report I describe a few specific examples of our ongoing work.
Although our human studies were essential for finding the gene and understanding the breadth of its clinical effects, we have many basic questions about the precise function of the CACP protein. For example, we want to know when and where this protein is expressed during skeletal formation and growth and, when it is genetically deficient, whether joint changes are present at birth, even though CACP symptoms do not begin until late childhood. We also want to know which portions of the gene are important for its correct expression in cartilage, which portions of the protein are essential to its biological function, and whether protein replacement can lessen joint damage. To address some of these questions, we are studying the expression of CACP protein during mouse development and we have created a mouse model of CACP by knocking out the gene in mice. We are also expressing different forms of the protein in vitro and are assessing each different form's effect upon cell growth, tissue localization, and surface lubrication.
Our goal is to replace protein function in our patients. Using the mouse model, we have begun exploring gene therapy and protein replacement therapy. We also want to know whether acquired alterations in this protein (with respect to its quantity, quality, or tissue localization) contribute to the common diseases of joints. Therefore, we are assessing CACP protein in cartilage and synovial fluid from cohorts of patients with rheumatoid arthritis and osteoarthritis. If we identify acquired changes in CACP protein among these patients, then therapies aimed at increasing endogenous protein synthesis or diminishing protein degradation may become valuable therapeutic adjuncts.
Another example of our interests is the osteoporosis-pseudoglioma syndrome (OPPG), a hereditary disorder that causes brittle bones. Children affected with this disease experience multiple fractures and often become wheelchair dependent. Bone biopsies from patients with OPPG suggest that bone fragility results from making too little bone, rather than an abnormal type of bone. Consequently, the gene responsible for causing OPPG is likely to be involved in the normal process by which bone quantity increases during growth. Since a risk factor for age-related osteoporosis is the amount of bone acquired during growth (that is, peak bone mass), the OPPG gene or the pathway in which it participates could be an important target for lessening the risk of osteoporosis in later life. We established an international consortium of patients, clinicians, and basic scientists to study OPPG (supported by grants from the Osteogenesis Imperfecta Foundation and the March of Dimes Birth Defects Foundation). The disease-causing gene we identified, LRP5, encodes a receptor that is expressed on the surface of bone-forming cells. This receptor recognizes and responds to members of the Wnt family of secreted growth regulators, suggesting an entirely new pathway by which bone mass can be regulated.
To delineate more precisely the pathway in which LRP5 participates, we are employing mouse models, organ culture models, and in vitro cell culture systems. In collaboration with a number of investigators, we are also exploring whether normal sequence variation in the LRP5 gene contributes to the normal variation in bone mineral density that occurs in human populations.
For our patients with OPPG, we are exploring whether we can use alternative methods to increase bone mass, such as bisphosphonates and parathyroid hormone administration, to alleviate their bone fragility symptoms. In the general population, the possibility that pharmacologic manipulation of the LRP5 pathway may safely improve bone mass accrual and dramatically reduce the worldwide incidence of osteoporosis is exciting.
In addition to the many rare genetic disorders that we study, my lab has also initiated studies of common skeletal diseases. During the past 5 years we have recruited patients undergoing joint replacement surgery for osteoarthritis for a study aimed at identifying genetic risk factors for end-stage joint disease (supported by a grant from the National Institutes of Health). We have interviewed more than 1,000 patients and collected detailed clinical and family histories. Our data suggest that normal genetic variation is a moderate risk factor for hip osteoarthritis, but not for knee osteoarthritis. Therefore, we have begun to focus our efforts solely on hip osteoarthritis and are deciding upon the most efficient way to search for the responsible genes. Four years ago, we initiated the Twins Bone Health Study, which currently comprises nearly 600 sets of healthy twin pairs recruited at the Twins Days festival in Twinsburg, Ohio; this annual event attracts more than 2,700 sets of twins. This large cohort of participants should allow us to delineate specific genetic and environmental factors that contribute to normal variations in bone strength.
Using human participants, model organisms, and in vitro systems, my lab is committed to understanding how genes, proteins, and biological pathways contribute to skeletal growth and homeostasis, and to apply the knowledge we gain from the study of patients with rare and common skeletal diseases to improve human health.
As of March 23, 2016