PTH Effects of Craniofacial Allografts

颅面同种异体移植物的 PTH 效应

• 批准号: 8522518
• 负责人: DAN GAZIT
• 金额: $ 28.61万
• 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/8522518
• 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; abstracting; 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; recombinase; reconstruction; regenerative; repaired; response; skeletogenesis; success; vasculogenesis

Abstract 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.

抽象的 虽然骨组织具有再生能力，可以自我修复骨折，但在极端情况下 如果骨质流失或损伤的程度过大，则不会发生完全再生。这样的 颅面复合体的骨缺陷通常是出生缺陷、外伤或癌症手术造成的。 口腔癌是下颌骨切除术和上颌骨切除术的主要原因；估计有 34,000 名美国人 今年全球将有超过40万人被确诊。此外，大约 1,600,000 每年都会进行骨移植，以再生因创伤或疾病而损失的骨质，其中 6% (96,000) 本质上是颅颌面。不幸的是，这些措施的长期结果 由于严重的组织纤维化和疤痕，颅颌面重建效果很差 发生在手术后。这种对移植生物材料的炎症、异物反应 仍然是治疗先天缺陷、创伤或创伤患者的巨大挑战之一 头部和口腔癌症。为了解决这些问题，这个多机构调查小组， 由免疫学家、肌肉骨骼科学家、组织工程师和临床医生组成， 双方长期合作，在该领域取得了多项进展。最近，我们 在治疗数名骨折不愈合患者方面取得了非凡的成功 通过手术使用重组甲状旁腺激素（PTH、特立帕肽），其中纤维状 诱导组织形成骨结合。基于此，我们启动了临床前研究来评估 特立帕肽在我们建立的大规模同种异体移植鼠股骨模型中的作用。我们的 初步结果表明，与正常的同种异体移植愈合相比，PTH： 1) 阻止形成 同种异体移植物皮质表面周围富含 3 型胶原蛋白 (Col3) 的纤维化组织，2) 减少 同种异体移植物周围的炎症和血管分布，3) 诱导大量的成骨细胞骨 结构同种异体移植物上和结构内的形成。因此，我们发现这种 PTH 反应非常类似于 活体自体移植物的“无疤痕”愈合。基于此，我们假设：1）PTH 治疗作用于 未分化间充质干细胞 (MSC) 被募集至手术部位，使其难以治疗 通常诱导疤痕形成的炎症纤维化信号； 2) PTH 治疗可以 用作佐剂以增加同种异体移植宿主连接处的膜内骨化，增加 同种异体移植物内部和周围的新骨形成，并减少炎症、血管化和 吓人。为了检验这些假设，我们将： 定义受 PTH 显着影响的生物标志物 无疤同种异体移植愈合过程中的治疗；并确定 PTH 诱导的无疤痕的细胞靶标 通过基因丧失和功能获得的研究来治愈。