PTH Effects of Craniofacial Allografts

摘要 虽然骨组织具有再生能力，能够在极端情况下自我修复骨折 如果骨丢失或破坏的程度过大，则不会发生完全再生。是这样的 颅面复合体的骨缺陷通常是由于出生缺陷、创伤或癌症手术造成的。 口腔癌是下颌骨和上颌骨切除的主要原因；据估计，美国有3.4万人 今年全球将有超过40万人被确诊。此外，约有160万人， 每年对因创伤或疾病丢失的再生骨进行植骨手术，占6% (96,000)本质上是颅颌面部。不幸的是，这些措施的长期结果 由于压倒性的组织纤维化和疤痕形成，颅颌面重建很差 发生在手术后。这种对移植的生物材料的炎性异物反应 仍然是治疗出生缺陷、创伤或创伤患者的巨大挑战之一 头部和口腔中的癌症。为了解决这些问题，这个多机构的调查小组， 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，在这一领域取得了几项进展。最近，我们 在治疗几例骨折不愈合的患者中取得了非凡的成功 使用重组甲状旁腺激素(PTH，Teriparatide)进行手术治疗，在这种情况下，纤维 诱导组织形成骨性愈合。基于此，我们启动了一项临床前研究，以评估 在我们所建立的同种异体大鼠股骨移植模型中，特瑞帕泰的作用。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)防止了 同种异体皮质面周围富含3型胶原(Col3)的纤维组织，2)减少 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 在同种异体结构移植物上和移植物中形成。因此，我们发现这种PTH反应非常类似于 活体自体移植的“无疤痕”愈合。在此基础上，我们假设：1)甲状旁腺激素治疗作用于 未分化间充质干细胞(MSC)被招募到手术部位，使其难以分化 正常情况下导致瘢痕形成的炎症-纤维化信号；以及2)甲状旁腺激素治疗可以 用作佐剂以增加同种异体移植宿主交界处的膜内骨化，增加 异体骨移植内及周围的新骨形成，并减少炎症，血管形成和 太吓人了。为了检验这些假设，我们将：定义明显受甲状旁腺激素影响的生物标志物 同种异体无瘢痕移植愈合过程中的治疗及甲状旁腺激素诱导的无瘢痕细胞靶点(S)的测定 通过基因缺失和功能研究的获得进行治疗。

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.