A Systems Approach to Understanding TMJDs
September 16-18, 2007
National Institute of Dental and Craniofacial Research
Temporomandibular Muscle and Joint Disorders Interagency Working Group
Meeting Summary and Report to the National Advisory Dental and Craniofacial Research Council
Contents
Topic: Page:
Executive Summary 2
Background 5
Description of the Disorder 5
Epidemiology 6
Federal Support of Research 6
TMJD Interagency Working Group 7
Recent NIH- and NIDCR-Sponsored Initiatives 9
Need For A New Approach 10
Discussion of Workshop Questions 12
Appendix 1: TMJDs – Research Needs and Opportunities 15
Appendix 2: Workshop Participants 19
Appendix 3: Meeting Agenda 20
Executive Summary
The Workshop participants were pleased to be invited to this unique Workshop as thought leaders to explore a new approach to a set of prevalent disorders that afflicts many patients and frustrates the healthcare community for lack of evidenced-based methods to treat these disorders. A systems approach to research and design is regularly used in engineering but is relatively new to biology. The approach is usually one of the studies of a process to determine a desired outcome and the most effective way of obtaining this outcome. In undertaking this approach one does not have an understanding of all (or perhaps any) of the intermediate steps. Systems approaches and analyses are powerful methods to compliment the reductionist research that predominates in biology.
The background and charge to the Workshop are presented subsequently. The presenters are all, except for Drs. Maixner and Clauw, new to the challenges of diagnosing, preventing and treating TMJDs. They provided a fresh examination of the field and thoughtful experience-based ideas of how to move the field forward. Based on the Workshop discussion, the participants created a set of guiding principles to guide the formation of specific recommendations for the NIDCR Council to consider. The overall goal of these principles is to support and translate research that addresses the needs and concerns of TMJD patients -
The recommendations should support research that:
- Uses integrative, interdisciplinary and interactive approaches
- Uses the best approaches and technologies available
- Insures that there is excellence in all programmatic aspects
- Identifies clear measurable goals with accountability for the deliverables with a
timetable - Enhances our understanding of the etiology and pathophysiology of TMJDs as well
as the intermediate phenotypes and their relationship to co-morbid conditions - Incorporates a balance between discovery and hypothesis testing within a systems framework (i.e., views TMJD not as an isolated disorder or condition but as part of an entire complex system which has many facets and connections)
- Is integrated horizontally in order to avoid ‘silo-building’ and to encourage involvement and collaboration among a wide variety of investigators with diverse perspectives, expertise and interests
- Develops a cadre of investigators on TMJD research by bringing experienced investigators in and training new investigators
- Builds upon and expands existing information and scientific resources (e.g., data sets available from OPPERA, other scientific studies involving TMJD/related conditions, patient organization databases, primary care providers) in order to advance current research, and encourage new questions/directions/avenues of research
- Represents a partnership between scientists, patients and funding agencies.
Most of the concluding discussion focused on the first question asked of the participants:
- Is the science sufficiently advanced to support a systems approach to the study of TMJDs?
There was a spectrum of opinions ranging from cautious optimism to uncertainty about the value of using systems approaches at this time. The thoughts on this question are outlined in the body of the report (pages 10-14). The members did not develop unanimous agreement on this question.
There was a fruitful discussion on possible research opportunities that could be undertaken if systems approaches were used. Based on the guiding principles and this discussion, the following research opportunities were considered. There was general agreement that if systems initiatives were planned, they include active management by the NIH-NIDCR.
Possible Research Opportunities
1) Support multidisciplinary research on the causes, pathophysiology, prevention, diagnosis and treatment of TMJDs.
a) Discovery and hypothesis driven research by co-principal investigators.
b) Resource human and animal databases available to applicants.
c) Annual research planning and investigator meetings.
d) Data network formatted for availability to everyone
2) Establish data-mining studies of clinical, patient advocacy and basic science databases (e.g., OPPERA, other chronic diseases, and TMJ Association Databases).
a) Genetic, environmental, therapeutic and management differences could be analyzed using bioinformatic systems models for specific outcomes, new associations and variances.
b) This could produce new hypotheses and new approaches for investigator-initiated research grant applications.
3) Implement TMJD training programs.
a) Summer program, nationally advertised, for introducing trainees to TMJDs.
b) Post-doc fellowships, research residencies, faculty exposure/retraining
(basic and clinical)
c) Mentoring and development of new faculty
Background
Description of the Disorder. Temporomandibular muscle and joint disorder (TMJD) is a complex heterogeneous condition. It likely represents a collection of disorders with varying etiologies, affecting the tissues of the masticatory muscles and the temporomandibular joint itself (TMJ). Due to this complexity and our lack of a complete understanding of the underlying mechanisms of disease onset and progression, the treatment for many patients with TMJD currently is less than satisfactory. The etiology and pathophysiology of complex disorders like TMJD may involve the interaction of genetic and environmental influences. In addition, there is likely a psychosocial set of factors that add to the complexity of TMJD, not only when considering diagnosis and treatment, but also in the context of pathological mechanisms associated with the disorder and other diseases that seem to coexist with TMJDs as co-morbidities. Peripheral defects in sensory neuron or muscle function, abnormal neurotransmission, central integration of sensory and motor inputs, and the societal and cognitive influences on these processes, may all interact and influence the pathological process and expression of associated chronic co-morbidities such as irritable bowel syndrome, fibromyalgia, chronic fatigue syndrome, multiple chemical sensitivity, cardiovascular abnormalities, and in some instances depression and anxiety.
The major symptoms of TMJD are chronic myofacial pain (particularly in the muscles of mastication), restricted range of jaw motion, jaw locking, and abnormal popping and clicking noises in the TMJ, although this latter symptom is not by itself either predictive or diagnostic of TMJD. In addition, other symptoms are known to occur in this disorder such as pain in the joint itself and in the area surrounding and radiating from the joint including the ear, neck, shoulder, and back; vertigo; diminished hearing or ringing in the ear; chronic headache; blurred or double vision; sleep disturbances; and difficulty in swallowing. Besides these symptoms, depression, anxiety disorders, and substance abuse may also be associated with TMJDs.
Epidemiology. It has been estimated that TMJDs affect approximately 10 million individuals, the majority of them women during their childbearing age. More recent epidemiological data, collected as part of the NIH-sponsored Osteoarthritis Initiative which includes both men and women, show that approximately 7% of 4796 individuals responding to questions about osteoarthritis pain, experienced pain in the jaw joint or in front of the ear during the 30 days prior to the survey. An additional 3.3% experienced facial or cheek pain or aching during the same 30 day period. Approximately 5.3% of those sampled expressed concern about the jaw/ear pain while only about 2.5% were concerned about the facial/cheek pain. When approximately 350 individuals were questioned about how long the joint/ear pain lasted or about any limitations caused by the pain, it was reported that the pain lasted for an average of approximately 9.0 days and that an average of approximately 1 day was lost to usual activities (e.g., work, school, etc) during the 30 days prior to the survey. Similar information collected from 157 individuals with pain in the face/cheek showed that it lasted an average of 9.8 days and kept individuals from usual activities for an average of 1.3 days. Responses to questions about the occurrence of pain during a period 6 or more months prior to the survey showed that approximately 6.8% had pain in the jaw joint or in front of the ear while approximately 3.1% had pain in the face or cheek 6 or more months prior to being queried.
Federal Support of Research. Research involving TMJDs has, for the most part, been from the National Institute of Dental and Craniofacial Research (NIDCR). A history of support between FY1996 and 2005, summarized in Table 1, shows that support has ranged between 3.4% and 5.1% of the total NIDCR research budget.
Table 1. NIDCR support of TMJD research (in $000).
TMJD Spending as a Percent of the Total NIDCR Research Budget FY1996 - 2005 | Fiscal Year | Percent of research budget | TMJD Spending | Total NIDCR Research budget |
|---|
| 1996 | 3.40% | 5,852 | 173,897 |
|---|
| 1997 | 3.40% | 6,426 | 188,941 |
|---|
| 1998 | 4.10% | 8,305 | 200,398 |
|---|
| 1999 | 4.80% | 10,547 | 219,658 |
|---|
| 2000 | 4.10% | 10,342 | 252,997 |
|---|
| 2001 | 4.40% | 12,824 | 288,878 |
|---|
| 2002 | 5.10% | 16,604 | 322,705 |
|---|
| 2003 | 3.40% | 11,861 | 351,837 |
|---|
| 2004 | 3.10% | 11,351 | 362,044 |
|---|
| 2005 | 4.10% | 15,122 | 369,902 |
|---|
Over the same period, as illustrated in Table 2, other ICs have increased their support for TMJD research from 2.8% to 24.5% of total NIH funding for TMJD research.
Table 2. NIH support of TMJD research by individual ICs (in $000).
NIDCR and Other Institutes Funding for TMJD
as a Percent of Total NIH Funding for TMJD Research | Participating ICs | FY1999 Actual | FY2000 Actual | FY2001 Actual | FY2002 Actual | FY2003 Actual | FY2004 Actual | FY2005 Actual |
|---|
| NIDCR | 10,547 | 10,342 | 12,824 | 16,604 | 11,861 | 11,351 | 15,122 |
|---|
| NIAMS | 0 | 0 | 165 | 187 | 71 | 77 | 563 |
|---|
| NINDS | 0 | 0 | 0 | 0 | 0 | 989 | 994 |
|---|
| NIMH | 0 | 0 | 0 | 0 | 115 | 0 | 0 |
|---|
| NIBIB | 0 | 0 | 0 | 100 | 330 | 735 | 972 |
|---|
| NCRR | 0 | 0 | 0 | 1,119 | 1,281 | 1,324 | 753 |
|---|
| NCCAM | 308 | 1,007 | 1,114 | 1,229 | 1,885 | 192 | 535 |
|---|
| OD | 0 | 0 | 414 | 1,024 | 821 | 2,020 | 1,087 |
|---|
| NIH | 10,855 | 11,349 | 14,517 | 20,263 | 16,364 | 16,688 | 20,026 |
|---|
| Other ICs total | 308 | 1,007 | 1,693 | 3,659 | 4,503 | 5,337 | 4,904 |
|---|
| |
| | FY 99 | FY 00 | FY 01 | FY 02 | FY 03 | FY 04 | FY 05 |
|---|
| NIDCR funding as % of NIH | 97.2% | 91.1% | 88.3% | 81.9% | 72.5% | 68.0% | 75.5% |
|---|
| Other IC's funding as % of NIH | 2.8% | 8.9% | 11.7% | 18.1% | 27.5% | 32.0% | 24.5% |
|---|
Temporomandibular Muscle and Joint Disorders Interagency Working Group (TMJDIWG). The TMJDIWG was established in 1998 in response to House and Senate Appropriation Committee Reports which encouraged the Institute to form an inter-institute committee. Dr. Tabak is the current Chairman of the TMJDIWG and Dr. Braveman is the Executive Secretary.
Current membership of the group includes representatives from: NIDCR, Office of Research on Woman’s Health (ORWH), National Center for Complementary and Alternative Medicine (NCCAM), National Heart, Lung and Blood Institute (NHLBI), National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Arthritis and Musculoskeletal Research (NIAMS), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institute of Deafness and Communication Diseases (NIDCD), National Institute of Drug Abuse (NIDA), National Institute of Neurological Diseases and Stroke (NINDS), National Institute of Nursing Research (NINR), Agency for Healthcare Research and Quality (AHRQ), Centers for Disease Control and Prevention: National Center for Health Statistics (NCHS), Food and Drug Administration (FDA), Centers for Medicare & Medicaid Services (CMS), and Department of Defense - National Naval Medical Center (NNMC). In addition, there are non-federal observers who attend the annual meeting including those representing the University of Cincinnati, The TMJ Association, the Jaw Joints & Allied Musculoskeletal Disorders Foundation, Inc., American Alliance of TMJ Organizations, and the Society for Women's Health Research.
The purpose of the TMJDIRWG is to serve as a summing point among federal agencies for research on TMJD, facilitating cooperation, communication and collaboration among member agencies. One of the activities of the group has been to develop a research agenda based on scientific needs and opportunities derived from recommendations of scientific meetings including those identified at the initial Technology Assessment Conference on TMJDs in 1997. These are included in Appendix 1. For the most part, each one of the areas identified in the catalogue is being addressed in part or whole by research currently supported by the NIH.
Recent NIH- and NIDCR-sponsored Initiatives. The catalogue has been used for the past several years by NIH and NIDCR in guiding the development of research initiatives. The following list summarizes some of the more recent ones, their purpose and the response to each:
Requests for Applications
New Models of Pain Relevant to the Trigeminal System, RFA: DE07-006, DE07-007
This Funding Opportunity Announcement seeks to stimulate research on chronic orofacial pain disorders that will provide insights into the pathophysiological mechanisms underlying these conditions and the biological mechanisms underlying analgesic treatments of these disorders. Two major goals of this initiative are 1) to stimulate research on patients with chronic painful disorders and 2) to stimulate the development and utilization of novel animal models of chronic orofacial pain conditions. As an adjunct to these two goals, this initiative also encourages the development of novel measures of pain in patients and animals that are non-invasive and objective and that permit a behavioral or functional assessment of pain. The primary outcome of this initiative will be increased knowledge of the biological mechanisms underlying chronic pain disorders, nociception, and analgesic therapies. Receipt date for applications: November 21, 2006, 42 applications were received, 11 funded/3 TMJD related
Collaborative Research on Tinnitus, RFA: DC07-004
The purpose of this Funding Opportunity Announcement is to support collaborative research teams to investigate tinnitus. Tinnitus can also be a symptom of other health problems. The NIDCR is interested in collaborative research proposals on tinnitus and the central mechanisms that may underlie this disorder. Tinnitus is a condition that may be comorbid with temporomandibular joint disorder (TMJD). TMJD is a chronic orofacial pain disorder that affects tissues surrounding the joint, including the ear. Ear ache, loss of hearing, and tinnitus are symptoms that have been associated with TMJD. The mechanisms responsible for these comorbidities are unknown, but recent research results suggest that central nervous system defects may play a role. The NIDCR is interested in applications from interdisciplinary teams of researchers exploring the biological mechanisms that are responsible for the association of tinnitus with TMJD. Receipt date for applications: November 29, 2006, received 12 applications/funding pending
The Role of Neuronal/Glial Cell Interactions in Orofacial Pain Disorders, RFA: DE06-005
The goal of this initiative is to stimulate basic research on the role of glial cells in pain disorders of the orofacial complex and in particular, studies on the interactions between glial cells and neurons that lead to pathological pain states. This initiative will encourage molecular, cellular, and animal studies on 1) the mechanisms by which stimulation of primary afferent nociceptors (neurons) lead to activation of spinal cord, brain, and peripheral glial cells; 2) the influence of activated glial cells (astrocytes and microglia) on nociceptive neuron function in experimental pain models; 3) the identification of glial cell proteins and signaling pathways important in maintaining chronic pain states; 4) the identification of the neuronal proteins and signaling systems regulated by activated glial cells; and 5) the role of activated microglia as antigen presenting cells influencing systemic immune cell interactions with the CNS. Received 29 applications, 6 funded/2 TMJD related.
Mechanisms of Orofacial Pain: Anatomy, Genomics and Proteomics, RFA: DE05-004
The purpose of this initiative is to encourage the use of genomic and proteomic approaches and imaging techniques to clarify the molecular events involved in: 1) acute orofacial pain, 2) the transition from unrelieved acute pain to chronic pain (i.e. neuroplasticity), 3) neuronal hyperexcitability as manifested by hyperalgesia and allodynia, and 4) chronic orofacial pain disorders of an inflammatory and neuropathic origin. This improved understanding could lead to new therapeutic interventions to effectively treat chronic pain conditions. Collaborative projects involving interdisciplinary teams of investigators are strongly encouraged. Received 15 applications, 3 funded/1 TMJD related.
Pathobiology of Temporomandibular Joint Disorders, RFA: DE03-005
The purpose of this initiative is to stimulate cross-cutting, integrative research aimed at delineating the mechanisms underlying the etiology and pathogenesis of the orofacial structures associated with Temporomandibular Joint Disorders (TMJDs). The ultimate goal of this initiative is a systems approach, from the gene, molecule, cell to tissue, and organ, that will provide the basis to better understand TMJDs and lead to the development of new insights into treatment and management of these disorders. Received 24 applications all of which were TMJD related; 10 funded
Program Announcements
Mechanisms, Models, Measurement and Management in Pain Research, PA06-544, PA06-543, PA06-542, PA07-282
The purpose of this Funding Opportunity Announcement is to inform the scientific community of the pain research interests of the various Institutes and Centers (ICs) at the National Institutes of Health (NIH) and to stimulate and foster a wide range of basic, clinical, and translational studies on pain as they relate to the missions of these ICs. Opening date September 1, 2006; first receipt date October 1, 2006, 165 applications received to date, 9 assigned to NIDCR
Temporomandibular Joint and Muscle Disorders: Pathophysiological Mechanisms Linking Comorbid Conditions, PA06-188, PA06-267, PA06-268, PA07-150
The purpose of this Funding Opportunity Announcement is to stimulate research on discovering etiological and pathophysiological mechanisms underlying a set of chronic, comorbid conditions associated with temporomandibular joint and muscle disorders (TMJDs). This program announcement seeks research applications that use state-of-the-art, multidisciplinary and interdisciplinary approaches to discover molecular, physiological, and behavioral mechanisms responsible for the overlapping symptoms manifested in the set of disorders that may co-exist with TMJMD. Opening date March 1, 2006; first receipt date October 1, 2006, 7 received, 7 assigned to NIDCR
Joint Degeneration: Mouse Models, PA04-139, PA06-450
The purpose of this Funding Opportunity Announcement is to stimulate research employing genetically defined and genetically modified mouse models to explore the biological mechanisms underlying non-inflammatory joint degeneration, or osteoarthritis. Applications received to date: 36, 3 assigned to NIDCR; 1 TMJD related funded
Need For A New Approach
Even though the Institute and NIH have devoted considerable resources to studying the etiology, pathogenesis and treatment of TMJDs, the development of effective preventive strategies and treatments has been illusive. Most recently the Institute has provided funding for a unique approach in studying TMJDs by funding the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study, a seven year multi-center prospective clinical study to identify risk factors that contribute to TMJDs. The PI is Dr. William Maixner, UNC-Chapel Hill, with other centers at the University of Florida, the State University of New York at Buffalo, and the University of Maryland at Baltimore. The study involves tracking 3,200 healthy volunteers for from 3 to 5 years in order to determine how many develop TMJDs and to assess the early stages of TMJDs including the genetic, biologic and behavioral factors that may contribute to the disorder and to pain sensitivity.
Parallel developments in biomedical research, specifically the growing popularity of systems biology in studying other complex diseases suggest that this approach may be helpful in unraveling the complexities of TMJDs. Thus the Institute and the TMJDIWG sponsored a two day workshop on a systems approach to studying complex diseases. The workshop was constituted as a sub-committee of the National Advisory Dental and Craniofacial Research Council and included Dr. Cecile Feldman as a co-chairperson and Drs. Matthew Doyle and Jon Levine as participants. A copy of the roster is found in Appendix 2 and the agenda is found in Appendix 3.
Leaders in systems research on a variety of complex diseases were invited to share with the group details of their approach to studying diseases including type II diabetes, cancer, peripheral pain disorders, cardiovascular disease, and epilepsy.
They were asked to address the following items in their presentations:
1. Describe the complex disease and what is currently known about it’s etiology and pathogenesis
2. What is meant by a systems approach in studying this disease – what is actually done?
3. Describe the research in the field at the time that you saw the need for a shift to a systems approach.
4. What were/are the barriers to making the shift – how were they overcome/ how are you attempting to overcome them?
5. What have been the benefits/costs in making the change?
6. Where is the field now with regard to an understanding of the disease?
7. What are the next steps?
In addition, Dr. William Maixner gave a presentation about the OPPERA study and Dr. Daniel Clauw spoke about his research on conditions that appear to co-exist with TMJDs.
Workshop participants were then asked to address the following questions as a way of arriving at recommendations for consideration by the NADCRC.
- Is the science sufficiently advanced to support a systems approach to the study of TMJDs?
- If so, is there a model of a systems approach that can/should be emulated or would a unique and different approach better serve future research on TMJDs?
- What are the advantages and disadvantages of these approaches?
- What options should be explored to develop a cadre of biologists, engineers, or clinicians to attack this problem?
Discussion of Workshop Questions
Is the science sufficiently advanced to support a systems approach to the study of TMJDs?
Most of the discussion focused on this initial question. There was a division among the participants. On the one hand, there were those who stated that the field is ready for the following reasons:
- Research on TMJDs seems to have benefited from larger initiatives such as OPPERA and, therefore, systems research should be the next step.
- There are currently definable hypotheses and theories ready to be addressed by investigative teams who have the expertise to do this using a hypothesis testing/theory driven approach. OPPERA is an example of a trans-institutional/trans-national approach of this type.
- It is important to develop a phenotype of TMJDs particularly as related to the co-morbidity of TMJD and other conditions. Taking a systems approach would allow the use of information from other clinical conditions to help clarify the phenotype.
- A systems approach would allow for the development of a pre-clinical model of TMJD either human or animal or both. The model would not be a TMJD or pain model but a clinical model which can be used to do mechanistic studies. There was a strong suggestion that the focus should be on humans since there is a very large behavioral component in TMJDs which could be lost if animal models are used. As an example, stress seems to play a large role in TMJDs or at least the pain component of it. Using a rat swimming model of stress, a popular one in use today, would likely miss the point of the qualitative and quantitative influences of stress in humans.
- We need to take advantage of modern technology. Research doesn’t need to be hypothesis testing but can be discovery research from humans and animals and a systems approach could be very effective in helping reach this goal.
- The current NIDCR portfolio of TMJD research is impressive and should continue. Supporting systems research would expand the scientific expertise brought to bear on the issue.
In contrast, others stated that a systems approach may be premature:
- Research on TMJDs could benefit from focus by interdisciplinary teams but at this point there is a lack of understanding of the TMJDs. It’s not like other complex diseases where there was a huge biological database available before a systems approach was developed and proved to be successful.
- While there is considerable evidence that TMJDs co-exist with other diseases (e.g., irritable bowel syndrome, fibromyalgia, and chronic fatigue syndrome) it is not clear how closely it is related to these diseases or to other similar diseases such as osteoarthritis of other joints.
- The ultimate goal of the research is develop sound information about risk factors and therapies. Data from the OPPERA study may lead us to both of these and it should be widely shared with others. However, at this point the full data set is still forthcoming and it is premature at this point to say what these data will show and whether their use in further analyses will be fruitful. Once these data are available , support should be provided for novel approaches to secondary data analysis.
If so, is there a model of a systems approach that can/should be emulated or would a unique and different approach better serve future research on TMJDs?
- As a first step, the data from OPPERA should be made available for use by others as a way of linking TMJDs to other conditions through secondary data analysis. Once this is completed we may be in a better position to move to a more traditional systems approach as currently configured for research on other complex diseases.
- An interdisciplinary research approach should be supported and would lead to the mechanisms which could then lead to the intermediate phenotypes of TMJDs.
- It is not clear what kind(s) of systems biology would be most appropriate nor are questions to be addressed clear…are we looking at orofacial pain or TMJDs? Further, it isn’t clear that we have the necessary building blocks to mount a large scale systems approach. At best, we would have to look at a subset of the conditions designated as TMJDs and it’s not clear that this is possible or desirable within the framework of a systems approach.
- The beginnings of research that would lead to a systems approach seem to be available however there are important missing pieces. For example, solid epidemiologic information about the incidence of TMJDs in the general population is not available. The PBRNs could be used to collect this kind of information. Further, patient databases could be mined for important information and could be used to begin building the network necessary for a full-fledged systems approach.
What are the advantages and disadvantages of these approaches?
This question was not addressed by the group.
What options should be explored to develop a cadre of biologists, engineers, clinicians to attack this problem?
- An interdisciplinary approach is needed and so these programs should be tapped for their expertise.
- This is high risk research requiring a safety net for those who make a commitment to research on it.
- Curricula need to be adapted to include solid scientific information about the epidemiology, prevention, etiology, pathophysiology and treatment of TMJDs. This could be accomplished at one or two Institutions in the US as well as through summer programs modeled on those at Woods Hole or Cold Spring Harbor.
- A mechanism should be developed to allow new, young investigators with training grants in TMJD to continue their projects at new Institutions as they transition to tenure-track or faculty positions.
Appendix 1
TMJDs - RESEARCH NEEDS AND OPPORTUNITIES
| I – Structure/Function |
| Evaluate the biomechanics of the TMJ |
| Clarify vascular structure and blood flow in relation to the metabolic demand of joint tissue |
| Evaluate the role of proprioceptive feedback in regulating jaw muscle function |
| Exploration of the integration of proprioception and nociception in the pattern generator circuitry of chewing |
| Determine the form and function of the craniomandibular structures in human subjects |
| Characterize temporomandibular joint tissues |
| Differential regulation of motor units within the craniomandibular structures in human subjects |
| II. Pathophysiology & Biomarkers |
| Development of a TMJ Registry to provide the clinical information whereby appropriate questions can be addressed in the human populations |
| Study postnatal growth, maturation, and aging in the normal TMJ and in response to injury |
| Identification of the mechanisms of injury and disease |
| Develop diagnostic criteria based on validated physiologic models of TMJ disease |
| Pathophysiological pathway identification and development of therapeutic strategies |
| Study nerve-vascular interactions to gain insight into mechanisms regulating joint growth and repair |
| Compare the processes controlling postnatal joint homeostasis with prenatal joint development |
| Examination of the genetic risk factors that may be involved with TMJ disease § Genetic contribution of both connective tissue elements and immunological elements § Transcription factors that control the processes of ossification and the development of growth plate § Abnormal distribution of proteoglycans in TMJ cartilage of heterozygous cho mice § Search for polymorphisms related to TMJ disorders |
| The role of crystalline Ca pyrophosphate dehydrate (CPPD) and basic Ca phosphate BCP in TMJDs to determine if therapeutic approaches can be developed to modify the development of these phosphate crystals in TMJ disorders |
| Early identification of bone resorption (imaging) |
| Role of subchondral bone loss in natural history of TMJ |
| Cause(s) and effects that the accumulation of microdamage and trabecular microfractures in subchondral bone may play in joint degeneration |
| Angiogenesis role in TMJ disorders and development of arthritis in the joint |
| Role of various inflammatory cytokines that participate in the development of pain and tissue destruction in the TMJ |
| Role of cytokines and other inflammatory processes in TMJ muscles and joints during trauma |
| Role of growth factors in pathophysiology and treatment |
| Role of estrogen (both genomic and non-genomic effects) in pathophysiology, including potential interactions between estrogen and growth factors |
| Role of gender and hormonal regulatory systems |
| Central procession and integration of afferent input from craniofacial region with that from non-craniofacial regions, which directly or indirectly innervate the same CNS region (key to co-morbidity factors) |
| Presence and role of acid-sensitive ion channels in jaw muscles and other deep tissues of the craniofacial region |
| Mediators of angiogenesis in joints compared to other structures |
| Angiogenic markers |
| o Anti-angiogenesis agents offer therapeutic benefit in TMJ |
| o Gene knock out mice |
| Determine whether genetic susceptibility to angiogenesis plays a role in susceptibility to the TMJ and related musculature |
| Examine muscle fatigue, persistent craniofacial pain paradigms and the state-dependent nature of these stressors upon quality of sleep and CV disorders |
| Animal and clinical studies to examine the capacity of cardiopulmonary, carotid sinus and aortic arch baroreceptor systems to regulate pain, autonomic function, motor functions and sleep |
| Value of arthrocentesis should be evaluated as a diagnostic and therapeutic modality |
| III. Pain |
| Role of glial cell activation and cytokine release in central and peripheral pathophysiology of craniofacial/deep tissue persistent pain |
| Relative role of central (including descending modulation) and peripheral plasticity (including effecter functions of afferent fibers) in mediating the onset of chronic pain in craniofacial regions |
| Changes in gene expression in the trigeminal ganglion, spinal cord, and brain in response to nociceptive stimuli using gene chip technology |
| Use of microarrays to determine what functional pathways may be responding to chronic pain |
| Elucidate peripheral mechanisms in TMJ pain |
| Elucidate the role of central mechanisms in TMJ pain |
| The origins and mechanisms responsible for pain in the masseter muscle of TMJ patients |
| The sensory neurons in masseter muscles and tendons to understand the origins of deep pain |
| Development of clinically relevant assays of nociception in human studies |
| Sensory, cognitive, affective, and other aspects of nociceptive stimulation on central processing (greater attention to sex and individual differences in response to nociceptive stimulation |
| Relative roles of central (including descending modulation) and peripheral plasticity (including effector functions of afferent fibers) in mediating the onset of chronic pain in craniofacial regions |
| Changes in gene expression in the trigeminal ganglion, spinal cord, and brain in response to nociceptive stimuli using gene chip technology |
| Pro-inflammatory cytokines used as biomarkers of pain associated with TMJ injury |
| Studies are required to understand mechanisms of persistent TMJ pain and to develop biomarkers of pain o Pain imaging o Improve and develop diagnostic approaches and criteria for defining TMJ diseases o Basis of co-morbidity of pain disorders o Research NGF in synovial fluid |
| IV. Changes in Cartilage |
| Turnover dynamics of the cartilage in a normal TMJ and that of patients with dysfunction |
| The role of apoptosis in cartilage degeneration of the TMJ needs to be explored |
| Regulation of the cartilage matrix turnover |
| Characterize the molecular structure of the TMJ – the proteoglycans and collagen types of all surface need to be determined |
| VI. Co-Morbidities and Diagnostics |
| Unique features of arthritis in the TMJ |
| Role of osteoporosis as a co-risk |
| Obtain clinical details describing the co-phenotypes related to TMJ disorders |
| Accurate assessment and categorization of patients using standardized techniques to enable normalization of data to compare patients |
| Clinical trials to assess the risks and benefits of this therapy in blocking the production of TNF-alpha |
| Determine if human masseter muscle types vary with clinical characteristics and whether this is the cause of consequence of the various clinical problems found in patients with TMJ disease |
| Development of new invasive and non-invasive investigative tools (e.g. nano-sensors of muscle and nerve activity, for imaging of airway and esophageal passages, for chronic delivery of molecules modulating pathway functions related to sleep, respiration, the heart, and blood vessels) to assess TMJ muscle and joint function, neural pathways, swallowing, respiration and related cardiovascular functions (e.g. for imaging these pathways) are required. |
| Development of TMJ in normal and diseased states |
| Basic epidemiological data to systematically document the incidence and/or prevalence of CV and sleep-related consequence of TMJ |
| Prospective clinical studies to determine if TMJD constitute a risk factor for CV disease |
| Studies aimed at providing an understanding of the shared biomechanical aspects of patients with TMJD and sleep disordered breathing |
| Various therapeutic modalities to evaluate the effects on the progression of arthritis in the TMJ of the TNF alpha transgenic mouse |
| VI. Treatment |
| Determine the effects of therapeutic drugs on tissue repair in temporomandibular diseases and disorders |
| Clarify tissue changes associated with foreign body reaction caused by alloplastic TMJ implants |
| The value of hyaluronic acid injections need evaluated |
| Management of oxidative stress associated with TMJ and associated muscles by biomechanical, biochemical and dietary approaches should be evaluated |
| Examine cellular mechanisms underlying the reported in vivo effectiveness of chondroitin sulfate and glucosamine hydrochloride in human degenerative TMJ disorders |
| Effects of therapeutic drugs on tissue repair in temporomandibular diseases and disorders |
| Evaluate novel reconstruction methodologies for temporomandibular diseases and disorders |
| Explore the potential for protein and gene therapeutic approaches to temporomandibular repair |
| Develop evidence-based protocols for the management of myofacial pain (without joint involvement) |
| Determine whether or not therapeutic strategies that focus on modulating the activity of cytokines are efficacious in TMJ disease |
| Apply principles of tissue engineering using mesenchymal stem cells to regenerate bone, cartilage, muscle, marrow stroma, and tendon and develop ways to deliver them to repair or regenerate injured temporomandibular structures |
| Role of exercise (nature and timing) in inhibition of hyperalgesia |
| VII. Animal Models |
| Animal models of OA to provide info about altered tissue composition or biomechanical properties and the pathways that are altered in cells |
| Develop new approaches and techniques using animal models to study the events associated with condylar resorption |
| TMJ pathology to develop experimental model systems to study underlying mechanisms of the disease |
| Consequences of changes in the masseter muscle strength and activity upon TMJ |
| Develop new model systems that better mimic the clinical features of craniofacial disorders, including those in which deep tissues are affected |
Appendix 2
Workshop Participants
*Cecile A. FELDMAN, DMD,
Workshop Co-Chair
Professor and Dean
University of Medicine & Dentistry of New Jersey
New Jersey Dental School
John T. WATSON, PHD,
Workshop Co-Chair
Associate Director of the William Von Liebig Center and Professor of Bioengineering
University of California at San Diego
**Atul J. BUTTE, MD, PHD
Assistant Professor
Stanford University School of Medicine
**Daniel J. CLAUW, MD
Professor
Medicine, Division of Rheumatology
Department of Internal Medicine
University of Michigan Medical School
**Allen COWLEY, PHD
Professor and Chair
Department of Physiology
Medical College of Wisconsin
**Raymond J. DINGLEDINE, PHD
Professor and Chair
Department of Pharmacology
Emory University School of Medicine
*Matthew J. DOYLE, PHD
Director & Senior Researcher
Health Care Research & Product Development – Worldwide
The Proctor & Gamble Company
**David J. GALAS, PHD
Professor
Institute for Systems Biology
**David E. HILL, PHD
Associate Director, Center for Cancer Systems Biology
Dana-Farber Cancer Institute
Janice K. KIECOLT-GLASER, PHD
Professor of Psychiatry and Psychology
Department of Psychiatry
College of Medicine
Ohio State University
*Jon D. LEVINE, MD, PHD
Professor, Medicine, Anatomy, Oral and Maxillofacial Surgery
Department of Anatomy
University of California at San Francisco
**William MAIXNER, DDS, PHD
Professor of Endodontics
Department of Endodonitcs
School of Dentistry
University of North Carolina at Chapel Hill
Mark A. MILANICK, PHD
Professor of Pharmacology and Phyisology
Dalton Cardiovascular Research Center
University of Missouri, Columbia
**Anne Louise OAKLANDER, MD, PhD
Associate Professor of Neurology
Department of Anesthesia and Critical Care
Massachusetts General Hospital
Harvard University Medical School
Frank SUITS, PHD
Senior Scientist
Computational Biology Center
IBM T.J. Watson Research Center
*Member NADCRC
** Presenter
Appendix 3
Meeting Agenda
A Systems Approach to Understanding TMJDs
September 16-18, 2007
National Institute of Dental and Craniofacial Research
Temporomandibular Muscle and Joint Disorders Interagency Working Group
September 16
Bethesda Marriott Suites
Introductions and Background Information
7:00 PM Welcome and Introductions:
Recent Advances in TMJD Research.……………Dr. Lawrence Tabak
Director
NIDCR
7:45 PM Goals and Organization of the Meeting...................Dr. John Kusiak
Program Director
NIDCR
8:00 PM Charge to Workshop Members……....... ...........…..Dr. Cecile Feldman
Dean
New Jersey Dental School
UMDNJ
Dr. John Watson
Professor
UC San Diego
8:30 PM A Systems Approach to Complex Diseases………Dr. David Galas
Institute for System Biology
9:00 PM Discussion
September 17
NIH Campus – Building 30 Room 117
Possible Models for a Systems Approach to TMJDs
8:30 AM TMJDs: The OPPERA Study………...........…………Dr. William Maixner
University of North Carolina
9:00 AM Discussion
9:30 AM TMJDs and Other Co-morbid Conditions.......…….Dr. Daniel Clauw
University of Michigan
10:00 AM Discussion
10:30 AM A Systems Approach in Studying Type II Diabetes………………..Dr. Atul Butte
Stanford University
11:00 AM Discussion
11:30 AM Break
11:45 AM A Systems Approach in Studying Hypertension…..Dr. Allen Cowley
Medical College of Wisconsin
12:15 PM Discussion
12:45 PM Lunch
1:30 PM A Systems Approach in Studying Peripheral Pain Disorder: CRPS
Dr. Anne Louise Oaklander
Massachusetts General Hospital
2:00 PM Discussion
2:30 PM A Systems Approach in Studying Epilepsy and Other Brain Disorders
Dr. Raymond Dingledine
Emory University
3:00 PM Discussion
3:15 PM Break
3:45 PM A Systems Approach in Studying Cancer…………………………..……………Dr. David Hill
Dana Farber Cancer Institute
4:15 PM Discussion
4:45 PM Panel Meeting and Discussion
7:00 PM Panel Meeting and Discussion at Bethesda Marriott Suites
September 18
NIH Campus – Building 30 Room 117
8:30 AM Presentation and Discussion of Panel Recommendations:
- Is there a model of a systems approach that can/should be emulated or would a unique and different approach better serve future research on TMJDs?
- What are the pros and cons of taking such an approach?
- In the absence of all necessary expertise existing in a single research area or setting, what options should be explored to develop a cadre of scientists, engineers and scientist clinicians to attack this problem?
11:30 AM Adjournment