PTH Effects of Craniofacial Allografts

描述（由申请人提供）：虽然骨组织具有能够自我修复骨折的再生能力，但在骨丢失或损伤程度过度的极端情况下，不会发生完全再生。颅面复合体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;估计今年将有34，000名美国人和超过400，000名世界各地的人被诊断出来。此外，每年约有1，600，000例骨移植手术，以再生因创伤或疾病而丢失的骨，其中6%（96，000例）为颅颌面骨。不幸的是，这些颅颌面重建的长期结果是穷人由于压倒性的组织纤维化和疤痕，发生手术后。这种对移植生物材料的炎症性异物反应仍然是治疗先天缺陷、创伤性损伤或头部和口腔癌症患者的巨大挑战之一。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小组一直在进行长期合作，在这一领域取得了一些进展。最近，我们在用重组甲状旁腺激素（PTH，teriparthrin）非手术治疗几例骨折不愈合的患者中取得了非凡的成功，这些患者中的纤维组织似乎被诱导形成骨愈合。基于此，我们开始了一项临床前研究，以评估特立哌酮在我们建立的小鼠股骨大块同种异体移植模型中的作用。我们的初步结果表明，与正常的同种异体移植物愈合相反，PTH：1）防止在同种异体移植物皮质表面周围形成富含3型胶原（Col 3）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）诱导在结构性同种异体移植物上和结构性同种异体移植物中形成大量成骨细胞骨。因此，我们发现这种PTH反应非常类似于活体自体移植物的“无瘢痕”愈合。基于此，我们假设：1）PTH治疗作用于募集到手术部位的未分化间充质干细胞（MSC），使其对通常诱导瘢痕形成的炎症纤维化信号不敏感;和2）PTH治疗可用作辅助以增加同种异体移植物宿主连接处的膜内骨化，增加同种异体移植物中和周围的新骨形成，并减少炎症，血管化和瘢痕化。为了验证这些假设，我们将：定义在无瘢痕同种异体移植愈合过程中受PTH治疗显著影响的生物标志物;并通过遗传丢失和功能获得研究确定PTH诱导的无瘢痕愈合的细胞靶点。 公共卫生相关性：虽然每年进行约100，000次骨移植以再生由于创伤或颅颌面疾病而丢失的骨，但由于手术后发生的压倒性组织纤维化和瘢痕形成，这些重建的长期结果很差。这种对移植生物材料的炎症性异物反应仍然是治疗先天缺陷、创伤性损伤或头部和口腔癌症患者的巨大挑战之一。最近，我们已经观察到骨质疏松症药物特立帕肽（重组甲状旁腺激素，PTH）在治疗骨折不愈合患者和骨移植动物模型中的显著效果，其中药物似乎可以溶解纤维化组织并防止异物反应。在这里，我们建议正式证明PTH具有这些作用，并可用作颅颌面重建手术的辅助治疗。

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.