PTH Effects of Craniofacial Allografts

摘要 虽然骨组织具有再生能力，能够自我修复骨折，但在极端情况下， 其中骨丢失或损伤的程度过度，将不会发生完全再生。等 颅面复合体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;据估计， 今年全球将有超过40万人被确诊。此外，约160万 每年进行骨移植，以再生由于创伤或疾病而丢失的骨，其中6% (96，000）是颅颌面的性质。不幸的是，这些长期的结果 颅颌面重建是差的，由于压倒性的组织纤维化和疤痕， 发生在手术后。移植生物材料的炎症性异物反应 仍然是治疗出生缺陷、创伤性损伤或 头部和口腔的癌症。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， 保持了长期的合作，在这一领域取得了一些进展。最近，我们 在治疗几例骨折不愈合患者方面取得了非凡的成功， 手术用重组甲状旁腺激素（PTH，teriparthritis），其中似乎纤维 诱导组织形成骨结合。基于此，我们启动了一项临床前研究， 在我们建立的大量同种异体移植的小鼠股骨模型中，观察特立派宁的作用。我们 初步结果表明，与正常的同种异体移植物愈合相反，PTH：1）阻止了 同种异体移植物皮质表面周围富含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，以及3）诱导大量的成骨细胞骨 在结构同种异体移植物上和内形成。因此，我们发现这种PTH反应与 活自体移植物的“无瘢痕”愈合。基于此，我们假设：1）PTH治疗作用于 未分化的间充质干细胞（MSC）募集到手术部位，使其难以治疗 通常诱导瘢痕形成的炎症纤维化信号;和2）PTH治疗可以 作为一种佐剂，以增加同种异体移植宿主连接处的膜内骨化， 在同种异体移植物中和周围形成新骨，并减少炎症、血管形成和 吓人为了验证这些假设，我们将：定义受PTH显著影响的生物标志物 无疤痕同种异体移植物愈合期间的治疗;并确定PTH诱导的无疤痕的细胞靶点 通过基因丧失和功能获得的研究进行治疗。

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.