Stephen I. Katz, M.D., Ph.D., NIAMS
William J. Sharrock, Ph.D., NIAMS
Lynda F. Bonewald, Ph.D., University of Missouri at Kansas City School of Dentistry
Introduction and Background
The NIAMS Bone Biology and Diseases portfolio covers a broad spectrum of research designed to better understand genetic and cellular mechanisms involved in the build-up and break down of bone. It includes studies on the regulation of bone remodeling; bone formation, bone resorption, and mineralization; and effects of hormones, growth factors, and cytokines on bone cells. It also maintains large epidemiologic cohorts for characterization of the natural history of osteoporosis, and for identification of genetic and environmental risk factors that contribute to bone disease.
The roundtable expanded on the feedback compiled by participants, as well as input received via a Web-based Request for Comments. Several themes emerged during the discussion.
Bone mineralization and remodeling
Studies of rare bone diseases have been responsible for insights into mechanisms of bone mineralization and remodeling, offering an abundance of knowledge that is disproportionate to their prevalence. Osteosclerosis, for example, provides a biologically relevant probe into wnt/beta-catenin signaling events in bone biology.
Bone is a storehouse for growth factors, which likely have multiple functions in vivo. The molecules also may behave differently when bound to matrix than in tissue culture solution.
Understanding the mechanisms by which matrix proteins affect mineralization could open avenues for new therapies. Participants speculated that whole families of proteins involved in bone mineralization and remodeling remain to be discovered.
The processes underlying mechanosensation and mechanotransduction also play crucial, biologically relevant roles in bone strength. The mechanism by which cells, both within and outside of the bone, communicate was another topic of considerable discussion.
Integrated physiology and pathophysiology
The research community is making considerable progress in understanding connections between the skeleton and organ systems or biologic processes that extend beyond bone as a structure and a mineral repository. Bone can be either a target or a regulator, and likely performs both roles as it interacts with various systems in development, aging, and disease. Much could be learned about bone biology from studies of other diseases, or treatments, that affect bone health or predispose people to fracture.
Although much work on bone metastases falls to the National Cancer Institute, the NIAMS is responsible for studies in which the primary focus is the bone and its biology.
Participants also were curious about the relationship between adipose and skeletal tissues, and possible differential effects of subcutaneous, visceral and marrow fat on bone. Unanswered questions about diabetes and bone health include the value of anti-resorptive therapies, the link between renal insufficiency and diabetic bone disease, and differences in calcification of blood vessels in diabetic and non-diabetic patients.
Multidisciplinary and interdisciplinary teams
Throughout the day, participants emphasized the importance of connecting disciplines and getting new and established researchers and clinicians to appreciate bone as an organ. Likewise, the bone community must include other disciplines and reach out to epidemiologists who have access to observational study cohorts.
As in other NIAMS roundtables, participants noted the need to develop analytical approaches suitable for systems biology studies and for a workforce trained in bio-mathematics, bio-informatics, quantitative reasoning, and statistics. Citing advances that stemmed from basic research following clinical concerns regarding osteonecrosis of the jaw, they also discussed the need to foster interactions between basic researchers and health care providers.
Inheritance of osteoporosis and other bone conditions - complex genetic influences
Thus far, most efforts to detect epigenomic chromosomal patterns have focused on stable, chronic pathologies that do not respond well to treatment. Epigenomic modifications also might underlie certain aspects of bone biology, such as the influence of aging. Proteomic studies may reveal post-translational modifications that researchers had not considered as important. Although there is little evidence for or against a role for microRNAs in osteoporosis, participants felt that hypothesis-driven studies of microRNAs might provide useful information for diagnosis or treatments.
Genome-wide association studies of continuously variable traits, such as bone mass, present special challenges. However, efforts to identify gene-gene interactions, and gene-environment interactions, may hold considerable promise for understanding the inheritance of osteoporosis.
Over the years, NIAMS-funded investigators have recruited thousands of people into studies where their bone mineral density and other relevant clinical parameters (including the incidence of fractures) have been characterized rigorously. If researchers could add high-density genotype information to the rich phenotypic data sets, the cohorts would be a valuable resource for studies to identify genetic risk factors, as well as new targets for therapeutic intervention.
Discovery of ancestry-associated markers is helping scientists to characterize research participants' racial backgrounds. This will strengthen efforts to elucidate any biological basis underlying racial differences in bone density and fracture risk, and may help to answer questions about correlations between vitamin D/calcium levels and fracture risk among races.
Bone quality and fracture risk
Although standard clinical measurement of bone density is widely available and economical, it only gives a rough estimate of bone quality and fracture risk. The research community would benefit from the ability to non-invasively monitor therapies' effects on bone quality, and identify people who display abnormal bone remodeling following treatments. Efforts to develop new imaging methods are ongoing that are appropriate for a variety of studies in adults and children.
Fracture healing and engineering/regeneration of bone
Although researchers have made considerable progress in developing promising new therapies to promote bone healing following a traumatic fracture or deliberate break during surgery, treatments for spontaneous osteoporotic fractures are less advanced.
Basic research on different types of stem cells was viewed as a productive area. Endothelial progenitor cells, for example, hold promise for skeletal repair. Advances in understanding heterogeneity of mesenchymal cell lineages, particularly when combined with appropriate scaffolds, also are expected to bear fruit. And, the ability to produce human induced pluripotent stem (IPS) cells has opened new avenues for exploration.
Promising therapies against bone diseases
Participants emphasized that the NIAMS must continue to play a leadership role in basic research to elucidate disease-specific pathogenic mechanisms and the cellular and molecular processes on which normal bone biology is based. Furthermore, understanding the mechanisms by which existing drugs strengthen bone or slow its loss should point the way to better therapies or combinations of therapies. Bone and the events responsible for bone heath are connected with other biologic processes; many drugs for conditions unrelated to bone may have anabolic effects.
Research needs to continue on unraveling disease mechanisms and applying therapies to different disease states. Anti-resorptive therapy is a widely accepted treatment of osteogenesis imperfecta, but the relationship between the collagen matrix and bone turnover rate is unclear.
Disease prevention and health promotion
Intervention trials show that loading exercises increase a child's bone mass. Because motivating behavior change at a population level is an issue facing many NIH components, it may be possible to integrate bone health messages with other health programs that include diet and exercise components. Likewise, the challenge of translating discoveries from clinical investigations into general practice is not unique to the bone community.
BELLIDO, Teresita M., Ph.D.
Professor, Department of Anatomy and Cell Biology
Indiana University School of Medicine
BONEWALD, Lynda F., Ph.D. (Co-Chair)
Professor, Department of Oral Biology
University of Missouri at Kansas City School of Dentistry
BOYCE, Brendan F., M.D.
Professor, Department of Pathology and Laboratory Medicine
University of Rochester Medical Center
CLEMENS, Thomas L., Ph.D.
Professor and Director, Division of Molecular and Cellular Pathology
University of Alabama at Birmingham School of Medicine
GUISE, Theresa A., M.D.
Professor of Medicine, Endocrinology and Metabolism
University of Virginia Health System
LIAN, Jane B., Ph.D.
Professor, Department of Cell Biology
University of Massachusetts Medical School
RAISZ, Lawrence G., M.D.
Director, Center for Osteoporosis
University of Connecticut Health Center
TEITELBAUM, Steven L., M.D.
Professor, Department of Pathology and Immunology
Washington University School of Medicine
TOWLER, Dwight A., M.D., Ph.D.
Lang Professor of Medicine, Barnes-Jewish Hospital
Washington University School of Medicine
ZMUDA, Joseph M., Ph.D.
Assistant Professor, Department of Epidemiology
University of Pittsburgh Graduate School of Public Health