Integrative Biology and Infectious Diseases Branch, DER, NIDCR
Objective
The objective of this concept is to encourage research on how the nervous system influences the formation and maturation, metabolism, homeostasis, and remodeling of the dental and craniofacial skeletal system (DCS). This effort will improve understanding of interactions between the peripheral and central nervous systems (PNS/CNS) and the DCS, and expand knowledge about the formation and maturation of mineralized tissues. The ultimate goal is to identify and utilize new insights to optimize normal function, reduce the impact of disease, and ideally develop capacity to repair or regenerate injured teeth and bones.
Background
Neuroskeletal biology—the interactions between the nervous system and mineralized tissues—is becoming an active area of research. The discovery that the nervous system influences bone formation and maintenance created a new paradigm. Bone is a mineral and matrix-dense tissue that comprises 12-15% of our body mass. Growing and maintaining it requires substantial energy. Bone remodeling, a life-long process, is a dynamic equilibrium where osteoblasts synthesize proteins to renew bone while osteoclasts resorb bone and release its stored resources for metabolism (Wee et al, 2016; Asada et al, 2015; Takeda 2008). Plus, as tissues mineralize, local cells become embedded as osteocytes that remain responsive to mechanical and chemical cues and continue to regulate homeostasis (Bonewald, 2011). The bone marrow, mineralized bone, and the periosteum are densely innervated, particularly by the thinly myelinated and unmyelinated “small-fibers” (e.g., C-fibers), that are requisite for bone health and contribute to bone disease. For instance, neural injuries can prevent broken bones from healing or cause heterotopic ossification; and axonopathy contributes to malformation or resorption of craniofacial bones and connective tissues in leprosy, neurofibromatosis-I, and the Parry-Romberg syndrome (Hurko et al, 2009).
More than a dozen ligands and receptors participate in communication cascades between bone and the nervous system, and neural signals affect bone volume and turnover (Spencer et al, 2004). Neurotrophic regulation of the sclerotome occurs directly and indirectly. Small-fibers not only transduce and transmit the pain sensation so characteristic of bone and tooth injuries, but they also secrete paracrine mediators from their distal terminals that bind to and influence bone cells. These include neuropeptide-Y (NPY), calcitonin gene related peptide (CGRP), and semaphorin-3 (Fukuda et al, 2013). The small-fibers also regulate other cells that influence mineralized tissues, in particular the small blood vessels, and immune cells. For instance they intimately contact mast cells, whose secretions including histamine, tryptase, and proinflammatory cytokines and chemokines, in turn affecting bone and potentiating inflammation (Greene et al, 2016). The CNS also contributes, influencing bone mass by mediators also involved in appetite and energy metabolism, including leptin, NPY, and cocaine- and amphetamine-regulated transcript (CART) - a neuropeptide precursor expressed in the hypothalamus. Leptin is a peptide hormone that not only binds to receptor in the hypothalamus to regulate appetite but also inhibits bone formation through sympathetic small-fiber axons that innervate the bone marrow. The cannabinoid receptor 2, which is abundant in osteoblasts, osteoclasts, and osteocytes and regulates bone homeostasis is also present on CNS microglial cells. Semaphorins, produced by osteoblasts and osteoclasts, also guide migrating neurites.
Investigators attracted to neuroskeletal biology have mostly focused on the appendicular bones and their diseases/conditions (Kumar et al, 2012; Farr et al, 2015), while DCS research has lagged. Earlier studies centered on regeneration in dental and pulpal tissues addressed only a few among the possible areas of investigation (Byers et al, 2003). This dearth is reflected in the scarcity of publications related to DCS versus interactions with long bones, hip, and spine. Given that osteoporosis also affects mineralized tissues of the DCS to reduce jaw length and density of alveolar bone (Straka et al, 2015) and that peripheral nerves and Schwann cells are functionally integrated with mineralized tissues (Adameyko et al, 2016), it stands to reason that the inter-tissue communication between the nervous system and DCS plays an essential role not only for the DCS but also for well-being of an individual in general.
Gaps and Opportunities
Dental and craniofacial mineralized tissues differ from appendicular mineralized tissues in embryological origins, mechanisms of mineralization and remodeling, microenvironment, and in types of mechanical forces experienced. Outflow to the trigeminal nervous system differs from that to the spinal system; and somatosensation, such as itch, differs (Michot et al, 2012; Oaklander et al, 2003). Findings from appendicular bones will not always apply to the DCS. Better understanding of neural-DCS crosstalk may be prerequisite for developing effective and specific therapeutics for conditions unique to the oral cavity such as dental caries, periodontal bone loss, or non-healing exposed bone from osteonecrosis of the jaw.
Findings that neural cells participate in the development and regeneration of the appendicular skeleton showcase the functional significance of the neuroskeletal axis throughout the lifespan. Disorders such as Moebius syndrome, in which individuals have skeletal malformations, cleft palate, and micrognathia, have also been shown to be a neurological disorder but with unknown etiology (Gutowski et al, 2015). While the importance of neuromodulation for DCS development and morphogenesis is recognized (Adameyko et al, 2016), we have just begun to learn its role in postnatal maintenance and regeneration of the DCS. A few older reports document neural effects on skull, teeth, and the temporomandibular joint (Atar et al, 2008; Yagasaki et al, 2003; Byrd et al, 2000), but they had little or no follow up, with only a few recent studies showing that craniofacial peripheral nerves regulate stem cells during tissue homeostasis and repair (Zhao et al., 2014; Kaukua et al., 2014; Feng et al., 2011). Renewed focus is needed. The role of the nervous system in DCS bone metabolism, homeostasis, and remodeling remains largely unexplored, and research on effects of neuropeptides in the DCS is largely limited to tooth pain and inflammation (Kyrkanides et al, 2016). Understanding neural maintenance of the postnatal DCS could conceivably enhance regeneration of craniofacial bones and teeth, with wide-ranging public health benefits. This initiative could provide powerful insights into counteracting the effects of aging and disease on the DCS.
Availability of new in vitro technologies that allow long-term co-culture of sensory neurons and non-neuronal tissues will aid these efforts (Neto et al, 2014). Additionally, new and developing in vitro “Tissues/Organs on Chip” technologies are increasing our ability to study complex systems of different cell types such as epithelial, neuronal, and stem cell (Ferreira et al, 2013). Combining these new tools and current genetic and proteomic capabilities should help dissect the roles of individual cells and molecules within these complex systems.
The scope of this initiative includes but is not limited to:
i. Identification and characterization of cellular and molecular mediators (e.g., stem/progenitor cells, receptors, agonists/antagonists, soluble ligands) involved in communication between the nervous system and the DCS
ii. Illumination of mechanisms responsible for specific effects of the nervous system on alveolar and craniofacial bone
iii. Elucidation of the effects of the nervous system on the teeth, including dentin, enamel, and cementum
iv. Elucidation of differential contribution of the nervous system to DCS homeostasis in health and/or disease compared to non-DCS tissues
v. Elucidation of the role of small-fibers in innervation of the DCS in health and/or disease
vi. Identification of postnatal molecular and cellular networks and pathways at the neural-DCS interface
vii. Examination of genetic, neurobiological, environmental, and endocrine factors that influence the neural-DCS interface, including sex-based differences
viii. Development of models to investigate the neural-DCS interface
ix. Development of strategies to harness neural effects on the DCS to ameliorate DCS diseases and potentially regenerate functional DCS tissues
This initiative will build on recent advances in skeletal and neuroskeletal biology, will take advantage of new tools and technologies in imaging, recording, and analyzing cell-cell and multi-tissue interactions, and will mobilize neuroskeletal scientists to focus on the DCS. Given its complexity, achieving the goals of this initiative will require multidisciplinary and interdisciplinary work among neuroscientists, dentists, bone biologists, bioengineers, and other professionals. Efforts such as the NIH Stimulating Peripheral Activity to Relieve Conditions (SPARC) and Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiatives could lay the foundation for additional investigation in neural-DCS interactions on the cellular and molecular levels. Many stakeholders are interested in promoting research on DCS health, and the National Osteoporosis Foundation pointed to interactions between bone and central nervous system as an important topic for research investment (Weaver et al, 2016).
Current Portfolio Overview
Studies of interactions between neural and musculoskeletal systems are currently primarily supported by NINDS and NIAMS. Among currently funded grants, few are exploring the topics above. Within NIDCR, recent efforts to establish a Dental, Oral, and Craniofacial Tissue Regeneration Consortium may also advance research in this area.
Individuals and Groups Whose Input was Solicited for This Initiative
NIAMS, NINDS, and NIDDK staff were consulted during the initial phase of this concept development.
Alignment with Institute Goals and Strategic Plan
This initiative is aligned with the
NIDCR Strategic Plan 2014-2019, Goals I and II, “Support the best science to improve dental, oral, and craniofacial health” and “Enable precise and personalized oral health care through research” respectively. Specifically, the initiative aligns with objectives I-1, I-2, and II-1 that “Enable basic research to advance knowledge of dental, oral, and craniofacial health”, “Promote development and use of comprehensive, interoperable databases and informatics resources to advance prevention, diagnosis, and treatment of dental, oral, and craniofacial diseases”, and “Support research toward precise classification, prevention, and treatment of dental, oral, and craniofacial health and disease”.
Selected References
1. The brain in bone and fuel metabolism. Wee, Kulkarni, Horsnell, Baldock. Bone. 2016 Jan;82:56-63. Review.
2. Communication of bone cells with hematopoiesis, immunity and energy metabolism. Asada N, Sato M, Katayama Y. Bonekey Rep. 2015 Oct 7;4:748.
3. Central control of bone remodelling. Takeda S. J Neuroendocrinol. 2008 Jun;20(6):802-7. Review.
4. The amazing osteocyte. Bonewald LF. J Bone Miner Res. 2011 Feb;26(2):229-38. Review.
5. Neurology and the skin. Hurko O, Provost TT. J Neurol Neurosurg Psychiatry. 1999 Apr;66(4):417-30. Review.
6. Emerging neuroskeletal signaling pathways: a review. Spencer GJ, Hitchcock IS, Genever PG. FEBS Lett. 2004 Feb 13;559(1-3):6-12.
7. Sema3A regulates bone-mass accrual through sensory innervations. Fukuda T, Takeda S, Xu R, Ochi H, Sunamura S, Sato T, Shibata S, Yoshida Y, Gu Z, Kimura A, Ma C, Xu C, Bando W, Fujita K, Shinomiya K, Hirai T, Asou Y, Enomoto M, Okano H, Okawa A, Itoh H. Nature. 2013 May 23;497(7450):490-3.
8. Endocrine manifestations of systemic mastocytosis in bone. Greene LW, Asadipooya K, Corradi PF, Akin C. Rev Endocr Metab Disord. 2016 May 30. Review.
9. Nerve dependence in tissue, organ, and appendage regeneration. Kumar A, Brockes JP. Trends Neurosci. 2012 Nov;35(11):691-9. Review.
10. Skeletal changes through the lifespan--from growth to senescence. Farr JN, Khosla S. Nat Rev Endocrinol. 2015 Sep;11(9):513-21. Review.
11. Dental neuroplasticity, neuro-pulpal interactions, and nerve regeneration. Byers MR, Suzuki H, Maeda T. Microsc Res Tech. 2003 Apr 1;60(5):503-15. Review.
12. Periodontitis and osteoporosis. Straka M, Straka-Trapezanlidis M, Deglovic J, Varga I. Neuro Endocrinol Lett. 2015;36(5):401-6. Review.
13. The Nervous System Orchestrates and Integrates Craniofacial Development: A Review. Adameyko, Fried. Front Physiol. 2016 Feb 19; 7:49.
14. Differential effects of calcitonin gene-related peptide receptor blockade by olcegepant on mechanical allodynia induced by ligation of the infraorbital nerve vs the sciatic nerve in the rat. Michot B, Bourgoin S, Viguier F, Hamon M, Kayser V. Pain. 2012 Sep;153(9):1939-48.
15. Herpes zoster itch: preliminary epidemiologic data. Oaklander AL, Bowsher D, Galer B, Haanpää M, Jensen MP. J Pain. 2003 Aug;4(6):338-43.
16. The congenital cranial dysinnervation disorders. Gutowski NJ, Chilton JK. Arch Dis Child. 2015 Jul;100(7):678-81. Review.
17. Of mice and mutations: phenotypic effects of the diabetic db/db and ob/ob mutations on the skull and teeth of mice. Atar M, Yasmin R, Sharma R, Le Comber SC, Verry P, Polly PD. Eur Arch Paediatr Dent. 2008 Mar;9(1):37-40.
18. The role of craniofacial growth in leptin deficient (ob/ob) mice. Yagasaki Y, Yamaguchi T, Watahiki J, Konishi M, Katoh H, Maki K.Orthod Craniofac Res. 2003 Nov;6(4):233-41.
19. Increased in vivo levels of neurotransmitters to trigeminal motoneurons: effects on craniofacial bone and TMJ. Byrd KE, Yang L, Yancey KW, Teomim D, Domb AJ. Anat Rec. 2000 Apr 1;258(4):369-83.
20. Secretion of shh by a neurovascular bundle niche supports mesenchymal stem cell homeostasis in the adult mouse incisor. Zhao H, Feng J, Seidel K, Shi S, Klein O, Sharpe P, Chai Y. Cell Stem Cell. 2014 Feb 6;14(2):160-73.
21. Glial origin of mesenchymal stem cells in a tooth model system. Kaukua N, Shahidi MK, Konstantinidou C, Dyachuk V, Kaucka M, Furlan A, An Z, Wang L, Hultman I, Ahrlund-Richter L, Blom H, Brismar H, Lopes NA, Pachnis V, Suter U, Clevers H, Thesleff I, Sharpe P, Ernfors P, Fried K, Adameyko I. Nature. 2014 Sep 25;513(7519):551-4.
22. Dual origin of mesenchymal stem cells contributing to organ growth and repair. Feng J, Mantesso A, De Bari C, Nishiyama A, Sharpe PT. Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6503-8.
23. Neurologic Regulation and Orthodontic Tooth Movement. Kyrkanides S, Huang H, Faber RD. Front Oral Biol. 2016;18:64-74.
24. Sensory neurons and osteoblasts: close partners in a microfluidic platform. Neto E, Alves CJ, Sousa DM, Alencastre IS, Lourenço AH, Leitão L, Ryu HR, Jeon NL, Fernandes R, Aguiar P, Almeida RD, Lamghari M. Integr Biol (Camb). 2014 Jun;6(6):586-95.
25. Interactions between developing nerves and salivary glands. Ferreira JN, Hoffman MP. Organogenesis. 2013 Jul-Sep;9(3):199-205. Review.
26. The National Osteoporosis Foundation’s position statement on peak bone mass development and lifestyle factors: a systematic review and implementation recommendations. Weaver CM, Gordon CM, Janz KF, et al. Osteoporosis International. 2016;27:1281-1386.
