While bone tissues have regenerative capabilities that enable self-repair of fractures, in extreme cases in which the extent of bone loss or damage is excessive, complete regeneration will not occur. Such bone defects in the craniofacial complex are often a result of birth defects, trauma or cancer surgery. Oral cancer is a major reason for mandibulectomy and maxillectomy;an estimated 34,000 Americans and over 400,000 people world-wide will be diagnosed this year. In addition, approximately 1,600,000 bone grafts are performed each year to regenerated bone lost due to trauma or disease, of which 6% (96,000) are craniomaxillofacial in nature. Unfortunately, the long-term results of these craniomaxillofacial reconstructions are poor due to the overwhelming tissue fibrosis and scarring that occurs following surgery. This inflammatory, foreign body response to the grafted biomaterial remains one of the great challenges in treating patients with birth defects, traumatic injuries or cancers in the head and mouth. To address these issues, this multi-institutional investigative team, comprised of immunologists, musculoskeletal scientists, tissue engineers and clinicians, has sustained a long term collaboration that produced several advances in this field. Most recently, we have achieved extraordinary success in treating several patients with facture non-unions non- surgically with recombinant parathyroid hormone (PTH, teriparatide), in whom it appears that fibrous tissue was induced to form a boney union. Based on this, we initiated a pre-clinical study to evaluate the effects of teriparatide in our established murine femur model of massive allografting. Our preliminary results indicate that in contrast to normal allograft healing, PTH: 1) prevents the formation of type 3 collagen (Col3) rich fibrotic tissue around the cortical surface of the allograft, 2) decreases inflammation and vascularity around the allograft, and 3) induces copious amounts of osteoblastic bone formation on and in structural allografts. As such we found that this PTH response closely resembles "scarless" healing of live autografts. Based on this we hypothesize that: 1) PTH therapy acts on undifferentiated mesenchymal stem cells (MSC) recruited to the surgical site, rendering them refractory to the inflammatory-fibrotic signals that normally induce scar formation;and 2) PTH therapy can be used as an adjuvant to increase intramembranous ossification at the allograft host junctions, increase new bone formation in and around the allograft, and decrease inflammation, vascularization and scaring. To test these hypotheses we will: define biomarkers that are significantly affected by PTH therapy during scarless allograft healing;and determine the cellular target(s) of PTH-induced scarless healing with genetic loss and gain of function studies.

Public Health Relevance

Although approximately 100,000 bone grafts are performed each year to regenerated bone lost due to trauma or disease that are craniomaxillofacial in nature, the long-term results of these reconstructions are poor due to the overwhelming tissue fibrosis and scarring that occurs following surgery. This inflammatory, foreign body response to the grafted biomaterial remains one of the great challenges in treating patients with birth defects, traumatic injuries or cancers in the head and mouth. Recently, we have observed remarkable effects of the osteoporosis drug teriparatide (recombinant parathyroid hormone, PTH) in treating patients with fracture non-unions and animal models of bone grafting, in which the drug appears to resolve the fibrotic tissue and prevent the foreign body reaction. Here we propose to formally demonstrate that PTH has these effects and could be used as an adjuvant therapy during craniomaxillofacial reconstructive surgery.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE019902-05
Application #
8473204
Study Section
Special Emphasis Panel (ZDE1-RW (11))
Program Officer
Lumelsky, Nadya L
Project Start
2009-06-15
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$567,223
Indirect Cost
$59,131
Name
University of Rochester
Department
Orthopedics
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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Jacobson, Justin A; Yanoso-Scholl, Laura; Reynolds, David G et al. (2011) Teriparatide therapy and beta-tricalcium phosphate enhance scaffold reconstruction of mouse femoral defects. Tissue Eng Part A 17:389-98

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