PTH Effects of Craniofacial Allografts

颅面同种异体移植物的 PTH 效应

• 批准号: 8073071
• 负责人: DAN GAZIT
• 金额: $ 34.38万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8073071
• 关键词: Address; Adjuvant; Adjuvant Therapy; Adult; Affect; Allografting; American; Animal Model; Autologous Transplantation; Biocompatible Materials; Biological Markers; Bone Tissue; Bone Transplantation; Calvaria; Cancer Patient; Cell Transplants; Cells; Child; Cicatrix; Collaborations; Collagen; Congenital Abnormality; Data; Defect; Diagnosis; Disease; Femur; Fibrosis; Foreign Bodies; Foreign-Body Reaction; Fracture; Gene Deletion; Gene Expression; Genetic; Genetic Models; Genetic Recombination; Head; Healed; Histology; Hormones; Image; Immunologist; Inflammation; Inflammatory; Injury; Isogenic transplantation; Knowledge; Life; Malignant Neoplasms; Mediating; Mesenchymal; Mesenchymal Stem Cells; Messenger RNA; Modeling; Mus; Musculoskeletal; Natural regeneration; Nature; Operative Surgical Procedures; Oral; Oral cavity; Osteoblasts; Osteogenesis; Osteoporosis; Parathyroid gland; Patients; Periosteal Cell; Periosteum; Pharmaceutical Preparations; Phase; Placebos; Process; Recombinants; Reconstructive Surgical Procedures; Recruitment Activity; Refractory; Risk; Role; Scientist; Signal Transduction; Site; Stromal Cells; Surface; Systemic Therapy; TNFSF11 gene; Tamoxifen; Teriparatide; Testing; Tissue Engineering; Tissues; Transcript; Transgenic Mice; Transplantation; Trauma; Undifferentiated; Vascular Endothelial Growth Factors; Vascularization; angiogenesis; base; bone; bone loss; bone morphogenetic protein 2; cancer surgery; cell type; cellular targeting; craniofacial; craniofacial complex; craniomaxillofacial; gain of function; graft healing; healing; hormone therapy; intramembranous bone formation; loss of function; malignant mouth neoplasm; mouse model; osteogenic; osteoprogenitor cell; preclinical study; prevent; programs; public health relevance; recombinase; reconstruction; regenerative; repaired; response; skeletogenesis; success; vasculogenesis

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：虽然骨组织具有再生能力可以使骨折自我修复，但在极端情况下，骨质流失或损害的程度过高，但不会发生完全再生。颅面复合物中的这种骨缺损通常是出生缺陷，创伤或癌症手术的结果。口腔癌是下颌骨切除术和上颌骨切除术的主要原因。今年将诊断出估计有34,000名美国人和全球40万人。此外，每年大约进行1,600,000个骨移植物，以使因创伤或疾病引起的再生骨损失，其中6％（96,000）本质上是颅颌面。不幸的是，由于手术后发生的压倒性组织纤维化和疤痕，这些颅颌面重建的长期结果很差。这种对移植生物材料的炎症性反应反应仍然是治疗头部和口腔中出生缺陷，创伤性损伤或癌症患者的巨大挑战。为了解决这些问题，这个由免疫学家，肌肉骨骼科学家，组织工程师和临床医生组成的多机构调查团队已经维持了长期的合作，在该领域取得了多次进步。最近，我们在与重组甲状旁腺激素（PTH，teriparatide）中非手术中的几名患者进行了非手术治疗方面取得了巨大的成功，其中似乎诱使纤维组织形成Bononey Union。基于此，我们启动了一项临床前研究，以评估teriparatide在我们已建立的大规模同种疗法的植物股骨模型中的影响。我们的初步结果表明，与正常的同种异体移植愈合相反，PTH：1）防止在同种异体移植物的皮质表面周围的3型胶原蛋白（COL3）富含纤维化组织的形成，2）降低了同种异体移植物周围的炎症和血管在结构同种异体移植物上诱导大量的成骨细胞骨形成。因此，我们发现这种PTH反应与现场自体移植物的“无疤”治愈非常相似。基于此，我们假设：1）PTH疗法作用于未分化的间充质干细胞（MSC）上招募到手术部位的，使它们对通常诱导疤痕形成的炎性纤维化信号难治性； 2）PTH疗法可用作增加同种异体移植宿主连接处的膜内骨化，增加同种异体移植物内及其周围的新骨形成，并减少炎症，血管性和恐惧。为了检验这些假设，我们将：定义生物标志物，这些生物标志物在同种异体移植愈合期间受到PTH疗法的显着影响；并确定PTH诱导的无疤痕愈合的细胞靶标，并通过遗传丧失和功能研究获得。 公共卫生相关性：尽管每年进行大约100,000个骨移植物，以使颅骨的创伤或疾病造成的再生骨骼损失，但这些重建的长期结果由于压倒性的组织纤维化和疤痕而发生的长期结果很差。 。这种对移植生物材料的炎症性反应反应仍然是治疗头部和口腔中出生缺陷，创伤性损伤或癌症患者的巨大挑战。最近，我们观察到骨质疏松症药物teriparatide（重组甲状旁腺激素，PTH）对治疗骨骼骨折的骨折和动物模型的患者的治疗患者似乎可以解决纤维化组织并防止异物反应，从而治疗骨骼嫁接的动物模型，以进行显着影响。 。在这里，我们建议正式证明PTH具有这些作用，可以用作颅面重建手术期间的辅助治疗。