Oral mucosa is uniquely known for its scarless and expedited wound healing compared to skin. Nonetheless, lines of evidence accumulate at the alarming rate that certain drugs used to treat bone- associated diseases specifically induce osteonecrosis of the jaw (ONJ) and delay wound healing of oral mucosa, leading to considerable clinical complications and compromising the patients' quality of life. The long- term users of these drugs, bisphosphonates (BP) and denosumab, are at the higher risk of developing ONJ, clinically defined as exposed necrotic bone with unhealed overlaying oral mucosa for at least 8 weeks. Both drugs have the common mechanisms of actions; they inhibit functions of osteoclasts, bone resorbing cells that are critically important for bone remodeling. However, the exact mechanisms as to why and how these bone- related drugs compromise the healing of the overlaying oral mucosal tissues are largely unknown. The lack of fundamental understanding in drug-induced ONJ is presumably due to the missing gaps in knowledge about osteomucosal healing, a combinatorial healing process of the soft and hard tissues as one entity that uniquely occurs in the oral cavity. To address this issue, we performed the high-throughput microarray analysis using the BRONJ mouse model at the sites of osteomucosal wounds and found series of differentially expressed genes including secretory proteins. We further developed a mouse model for DRONJ and found similar ONJ-like lesions. Based on our preliminary studies, we hypothesize that the osteomucosal wound healing is orchestrated by cross interactions among cells in soft and hard tissues via secretory proteins at the site of wound, and that drug-induced ONJ is developed by deregulating such interactions by BP and denosumab, leading to distinct molecular alterations and impaired osteomucosal healing. The objectives of this proposal are: 1) to investigate role of RANKL, a secretory protein important for bone remodeling and healing, using genetically engineered mice; 2) to identify genes/proteins that are commonly deregulated in BRONJ- and DRONJ-like lesions using the high-throughput microarray and proteomics; and 3) to investigate the cross interactions between different cell types using co-culture systems as well as our newly developed osteomucosal tissue constructs in vitro. Oral mucosal tissues are anatomically situated in close proximity to the underlying bone tissues, suggesting that the drug-induced ONJ in the oral cavity may be associated with the impaired cross-talks between these two entities during the osteomucosal wound healing processes. Current proposal would help unraveling the molecular mechanisms of rather unexplored areas of research in osteomucosal wound healing and provide knowledge for future therapeutic applications to both BRONJ and DRONJ.

Public Health Relevance

A growing body of evidence accumulates that bisphosphonates and denosumab, drugs used to treat bone- diseases, not only cause osteonecrosis of the jaw (ONJ) but also impair oral mucosal wound healing. However, the reasons as to why and how these bone-related drugs compromise healing of the overlaying oral mucosal tissues are largely unknown. In this proposal, we will examine the pathophysiology of bisphosphonate- and denosumab-related ONJ (BRONJ and DRONJ) by investigating the mechanisms of osteomucosal healing - the combinatorial healing of the soft and hard tissues as one entity that uniquely occurs in the oral cavity - in the mouse models for BRONJ and DRONJ.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE023348-03
Application #
8847574
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wan, Jason
Project Start
2013-09-13
Project End
2016-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Shah, A; Lee, D; Song, M et al. (2018) Clastic cells are absent around the root surface in pulp-exposed periapical periodontitis lesions in mice. Oral Dis 24:57-62
Song, Minju; Yu, Bo; Kim, Sol et al. (2017) Clinical and Molecular Perspectives of Reparative Dentin Formation: Lessons Learned from Pulp-Capping Materials and the Emerging Roles of Calcium. Dent Clin North Am 61:93-110
Lee, Rachel S; Sohn, Suhjin; Shin, Ki-Hyuk et al. (2017) Bisphosphonate inhibits the expression of cyclin A2 at the transcriptional level in normal human oral keratinocytes. Int J Mol Med 40:623-630
Song, Minju; Kim, Sol; Kim, Terresa et al. (2017) Development of a Direct Pulp-capping Model for the Evaluation of Pulpal Wound Healing and Reparative Dentin Formation in Mice. J Vis Exp :
Kim, Sol; Williams, Drake W; Lee, Cindy et al. (2017) IL-36 Induces Bisphosphonate-Related Osteonecrosis of the Jaw-Like Lesions in Mice by Inhibiting TGF-?-Mediated Collagen Expression. J Bone Miner Res 32:309-318
Lee, Sung Hee; Rigas, Nicole Kristina; Lee, Chang-Ryul et al. (2016) Orai1 promotes tumor progression by enhancing cancer stemness via NFAT signaling in oral/oropharyngeal squamous cell carcinoma. Oncotarget 7:43239-43255
Lee, Sung Hee; Park, Yongtae; Song, Minju et al. (2016) Orai1 mediates osteogenic differentiation via BMP signaling pathway in bone marrow mesenchymal stem cells. Biochem Biophys Res Commun 473:1309-1314
Lee, Chang-Ryul; Lee, Sung Hee; Rigas, Nicole Kristina et al. (2016) Elevated expression of JMJD6 is associated with oral carcinogenesis and maintains cancer stemness properties. Carcinogenesis 37:119-128
Kim, Reuben Han-Kyu; Yang, Paul; Sung, Eric C (2016) Managing Intraoral Lesions in Oral Cancer Patients in a General Dental Practice: An Overview. J Calif Dent Assoc 44:85-92
Song, Minju; Alshaikh, Abdullah; Kim, Terresa et al. (2016) Preexisting Periapical Inflammatory Condition Exacerbates Tooth Extraction-induced Bisphosphonate-related Osteonecrosis of the Jaw Lesions in Mice. J Endod 42:1641-1646

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