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 尽管骨组织具有再生能力可以使骨折的自我修复，但在极端情况下 其中骨质流失或损害的程度过大，不会发生完全再生。这样的 颅面复合物中的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。估计有34,000名美国人 今年将诊断出全球超过40万人。此外，大约1,600,000 每年进行骨移植，以使因创伤或疾病引起的再生骨骼损失，其中6％ （96,000）本质上是颅颌面。不幸的是，这些结果的长期结果 颅颌面重建由于压倒性的组织纤维化和疤痕而贫穷 手术后发生。这种炎症性异物对接枝生物材料的反应 仍然是治疗出生缺陷，创伤性伤害或 头和嘴里的癌症。为了解决这些问题，这个多机构调查团队， 由免疫学家，肌肉骨骼科学家，组织工程师和临床医生组成 持续了一项长期合作，在该领域取得了多个进步。最近，我们 在治疗几名forture非工会的患者方面取得了极大的成功 手术与重组甲状旁腺激素（PTH，Teriparatide），在其中看来是纤维 组织被诱导形成骨骼联合。基于此，我们开始了一项临床前研究以评估 Teriparatide在我们已建立的大规模同种植物的鼠股股模型中的影响。我们的 初步结果表明，与正常同种异体移植愈合相反，PTH：1）防止形成 3型胶原蛋白（COL3）围绕同种异体移植的皮质表面富含纤维化组织，2）减少 同种异体移植周围的炎症和血管，3）诱导大量成骨细胞骨骼 结构同种异体移植物上的形成。因此，我们发现这种PTH响应与 现场自体移植的“无疤”治疗。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）招募到外科部位，使其难治性 对于通常诱导疤痕形成的炎性纤维化信号； 2）PTH疗法可以是 用作同种异体移植宿主连接处增加膜内骨化的佐剂，增加 同种异体移植物内外的新骨形成，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 在无疤的同种异体愈合期间的治疗；并确定PTH诱导的无疤的细胞靶 通过遗传丧失和功能研究的增益进行愈合。