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Opportunities and Challenges in Bone Biology and Diseases
Monday, November 18, 2011
NIH Campus, Building 31, Room 6C10
9:00 AM – 4:00 PM
Background and Approach
The NIAMS regularly seeks to inform its long-range planning and priority-setting process with input from the scientific community. This roundtable discussion, one of several in 2011 that together covered a broad range of scientific areas within the NIAMS mission, focused on bone biology and bone diseases. Studies of the biology and medicine of bone are critical not only for our understanding of health problems that manifest in bone itself, but also for our approaches to areas that were the focus of other 2011 roundtable meetings, such as musculoskeletal tissue engineering, and the degenerative and autoimmune arthritis.
In advance of the meeting, participants were encouraged to consult with colleagues on the following questions:
- What are the most promising areas of science for advancing our knowledge of bone biology and bone diseases? What are the most important gaps in our understanding of bone biology and bone diseases? What are the most needed resources or methodologies to fill the gaps?
- What are the greatest challenges, other than workforce issues, to research progress? What are the potential options for overcoming these challenges?
- What can the NIAMS do to facilitate translation of basic research into benefits for patients and the public?
- What gaps in training have delayed progress in critical research areas?
- What innovative, creative approaches are needed to transform the understanding of health disparities as they relate to bone diseases?
Although only a subset of topics were discussed in depth and are summarized here, NIAMS leadership and the appropriate program staff read each comment. The NIAMS greatly appreciates the community’s input on these questions.
Time was also reserved to discuss strategies to maintain the vitality of the scientific enterprise in an era of fiscal challenges.
Promising Areas of Science and Pressing Research Needs
Based on participants’ comments received in advance of the meeting, several broad areas of interest emerged.
Biomarkers of Bone Quality
Fracture risk is a complex function of bone mass, architecture, and material properties. Current assessment of fracture risk includes use of both biochemical (bone turnover) and structural (bone mineral density) biomarkers. However, currently accepted assessments lack both sensitivity and specificity with regard to actual fracture risk. Continuing development of imaging technology has the potential to provide clinically useful indicators of bone strength, based on bone structure and mathematical modeling, which has shown somewhat better correlation with fracture. A clearer understanding of the factors that influence the degree of mineralization of bone could also lead to improved markers for bone strength. Several participants mentioned the potential utility of markers of bone strength that could replace fractures as endpoints in clinical trials. Much discussion focused on differences between research and clinical needs, and the data required by the FDA before it will accept a biomarker as a surrogate.
Basic Research That May Lead to Therapies
Much of the potential for novel therapeutic development resides in recent insights into the roles of osteocytes. These matrix-embedded cells are already viewed as an important target of anabolic therapies, and much remains to be learned about their communication with bone-forming osteoblasts. In addition, their recently appreciated potential to influence the activity of bone-resorbing osteoclasts suggests a complexity that needs to be considered when developing new drugs that will alter bone homeostasis. The coupled nature of bone formation and resorption has limited some therapeutic approaches. Thus, compounds that increase the bone-building properties of osteoblasts in the presence of anti-resorptive agents also have therapeutic potential. Furthermore, stem cells in the bone marrow are another potential anabolic target, if safe, effective compounds could be developed that encourage differentiation into osteoblasts.
Compared with the mechanisms at work in the endosteal compartment (where bone is in contact with the marrow), the events that lead to the development and maintenance of the outer surface of the cortex (which is in contact with the periosteum) are relatively understudied. Although the cortex is an important factor in bone strength, many details of biology at the periosteal surface, including the source of progenitor cells for osteoblasts and osteoclasts, remain unclear.
Laboratory mice in which researchers have inactivated (i.e., "knocked out") an existing gene by replacing it or disrupting it with an artificial piece of DNA, have become an essential tool for probing the functional roles of specific genes. Although NIH-funded resources such as the Knockout Mouse Project (KOMP; http://www.genome.gov/17515708), and the Mutant Mouse Regional Resource Centers have facilitated access to valuable mouse strains, researchers suggested that more could be done. In particular, phenotypic information on knockout strains is sparse and not always readily available. The Knockout Mouse Phenotyping Program (http://commonfund.nih.gov/KOMP2/) is a welcome step, but does not include many phenotypic measures that would be relevant to NIAMS mission areas.
Often, crucial experiments require that genes be knocked out only in certain tissues or at certain times during development. Generation of such strains depends on the availability of “driver” strains, most often expressing the Cre recombinase in specific cells or tissues. Some researchers have found that Cre driver strains are not easily available or, if available, are not well characterized, impeding progress on a number of important problems. At the same time, researchers must recognize that existing mouse resources are based on a very few inbred strains, and seek ways of testing conclusions in more diverse genetic backgrounds.
Integration of Research on Bone with the Study of Other Tissues and Organ Systems
Recent years have brought demonstrations of functional links between bone and a number of other tissues and organ systems, including those involved in phosphate homeostasis and energy metabolism, the immune and hematopoietic systems, the nervous system, and muscle. Trans-disciplinary collaborations are becoming increasingly important as researchers develop a greater appreciation for bone as a component of broader metabolic and regulatory networks. Researchers who have traditionally focused on bone biology will increasingly need to collaborate with investigators who have expertise in different organ systems in order to bring new concepts and new methodologies to bear on problems involving bone.
The separation between traditional scientific disciplines and clinical specialties can present barriers to the establishment of such collaborations. Broader communication, both formal and informal, between different groups of scientists could help to build the necessary bridges. Participants noted the potential for the field of skeletal health to be informed by, and to illuminate in turn, areas of health and medicine including obesity, cardiovascular disease, diabetes, and kidney disease.
Building on Conceptual and Technical Advances in our Understanding of the Genome, Epigenome, Transcriptome, and Proteome
Technological and scientific advances arising from the Human Genome Project and the International HapMap Project are beginning to be leveraged to identify rare and common genetic variants that influence complex skeletal phenotypes. As results accumulate from genome-wide association studies, applying the findings to identify new molecular pathways related to bone health and disease becomes the next challenge. Studies of clinical bone mineral density indicate that a large number of genes contribute to skeletal phenotype. Participants identified several approaches with the potential to resolve this complexity:
- Systems biology, which offers computational tools for modeling the net effects of large numbers of interacting components, and for combining information from different biological levels, such as genetic variation, epigenetics, gene expression, and phenotype.
- Mouse genomics, which has the potential to test gene function in knockout strains, and to generate phenotypic diversity through recombination of inbred strains, providing an independent test of the relationship between genetic variation and phenotype.
- Human genomics, which now extends beyond single nucleotide polymorphisms to include copy number variation and structural rearrangements such as insertions and deletions. Promising areas include the human epigenome, transcriptome, micro-RNA and other non-coding RNAs, and gene-gene/gene-environment interactions.
The increasing importance of genomic- and systems-based approaches brings challenges related to the scale of the data generated with high-throughput technology and the specialized bioinformatics and computation expertise necessary to make use of the data. This area will need creative approaches for the establishment and maintenance of shared resources, and for the training and career development of researchers with the appropriate skills.
Translating Basic Science Advances into Clinical Practice
Noting that support for many large clinical trials is outside the scope of the NIAMS budget, participants emphasized the potential of partnerships with industry, as well as the role the Institute could play in supporting proof-of-principle or first-in-human clinical studies that could later garner commercial support. NIAMS’ clinical trials initiatives aspire to fill this need.
Efforts to translate basic research findings into clinical practice will benefit from greater interaction between basic and clinical scientists and may be facilitated by NIH-funded core resources available at local institutions through the Clinical and Translational Science Awards (CTSA) program, now part of the National Center for Advancing Translational Sciences (NCATS). Other opportunities may arise through programs such as the Patient-Centered Outcomes Research Institute (PCORI) [as outlined in the Patient Protection and Affordable Care Act (Public Law 111-148)].
The discussion identified a number of innovations that could significantly change the ways in which translational research is done, including the development of shared bioinformatics resources, the potential development of disease-specific models using induced pluripotent stem cells, and the incorporation of health care networks into the design and execution of clinical studies.
In response to concerns that a focus on translation of new discoveries to therapies could disadvantage basic science, NIAMS leadership emphasized that the balance between basic and applied research supported by the NIH has remained essentially constant for many years, and that the NIAMS is committed to maintaining the current balance.
Training the Next Generation of Researchers
The growing importance of inter- or trans-disciplinary teams presents challenges for the training and career development of the next generation of investigators. Mentors may find that they lack some of the resources and knowledge they need to guide young scientists whose developing research interests require collaboration with members of communities outside the mentors’ experience. This challenge might be met by the formation of mentoring teams, incorporating a diversity of expertise. An institutional research environment that fosters communication and collaboration between disciplines could also enhance training and career development. Finally, students would be well-served by opportunities to develop communication, leadership, and advocacy skills, in addition to the scientific and technical skills more often emphasized for a career in academic research.
Eliminating Disparities in Treatments and Outcomes among Racial and Ethnic Groups
African ancestry is generally seen as protective against fracture, relative to European ancestry. However, the reality of disparities in bone health is more complex. African American women are more likely to die after hip fracture, and are less likely to be able to walk independently upon release from the hospital. This may be due largely to the fact that they tend to be older than white women when they suffer a hip fracture, and also suffer from more comorbidities (e.g., diabetes, chronic kidney disease, obesity) which could lessen their ability to recover. Although environmental factors are very likely involved as well, the emerging biological links between bone, energy metabolism, and kidney function suggest that there is much to be learned from examining how the operation of this regulatory network differs in people of different racial and ethnic backgrounds. Because most epidemiologic and genetic studies of bone health to date have focused on women of European ancestry, there is currently a lack of data in other groups.
Maintaining the Vitality of the Scientific Enterprise in an Era of Fiscal Challenges
It is expected that the resources available to support biomedical research will remain flat at best, and possibly contract, in the foreseeable future. Because all sectors of the research community are committed to supporting robust research programs and maintaining the scientific work force in the current budget climate, time was reserved for participants to discuss scenarios and data posted by the NIH Office of Extramural Research at:
- “Rock Talk” (http://nexus.od.nih.gov/all/2011/10/17/how-do-you-think-we-should-manage-science-in-fiscally-challenging-times/)
- Ways of Managing NIH Resources presentation (http://report.nih.gov/UploadDocs/Ways%20to%20Manage%20Final.pdf)
Participants recognized a number of factors that are necessarily in tension when considering the impact of various measures. Simply allowing the application success rate to decline with the available resources risks reducing the breadth of concepts and approaches at work in the enterprise to the point where innovation would suffer. On the other hand, reducing the average award size across the board could make some laboratories that depend on a single grant unsustainable. Salary limitations might prompt institutions to require clinicians to spend extra time seeing patients, which could limit their involvement in research. Long-standing concern about how to encourage trainees and junior investigators to commit to a research career could only grow if some protection is not afforded those in the early stages of research careers.