James Aaron W, Shen Jia, Tsuei Rebecca, Nguyen Alan, Khadarian Kevork, Meyers Carolyn A, Pan Hsin Chuan, Li Weiming, Kwak Jin H, Asatrian Greg, Culiat Cymbeline T, Lee Min, Ting Kang, Zhang Xinli, Soo Chia
Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
UCLA and Orthopaedic Hospital Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, Los Angeles, California, USA.
JCI Insight. 2017 Jun 15;2(12). doi: 10.1172/jci.insight.92573.
NELL-1 is a secreted, osteogenic protein first discovered to control ossification of the cranial skeleton. Recently, NELL-1 has been implicated in bone maintenance. However, the cellular determinants of NELL-1's bone-forming effects are still unknown. Here, recombinant human NELL-1 (rhNELL-1) implantation was examined in a clinically relevant nonhuman primate lumbar spinal fusion model. Prolonged rhNELL-1 protein release was achieved using an apatite-coated β-tricalcium phosphate carrier, resulting in a local influx of stem cell antigen-1-positive (Sca-1+) mesenchymal progenitor cells (MPCs), and complete osseous fusion across all samples (100% spinal fusion rate). Murine studies revealed that Nell-1 haploinsufficiency results in marked reductions in the numbers of Sca-1+CD45-CD31- bone marrow MPCs associated with low bone mass. Conversely, rhNELL-1 systemic administration in mice showed a marked anabolic effect accompanied by increased numbers of Sca-1+CD45-CD31- bone marrow MPCs. Mechanistically, rhNELL-1 induces Sca-1 transcription among MPCs, in a process requiring intact Wnt/β-catenin signaling. In summary, NELL-1 effectively induces bone formation across small and large animal models either via local implantation or intravenous delivery. NELL-1 induces an expansion of a bone marrow subset of MPCs with Sca-1 expression. These findings provide compelling justification for the clinical translation of a NELL-1-based therapy for local or systemic bone formation.
NELL-1是一种分泌型成骨蛋白，最初被发现可控制颅骨的骨化。最近，NELL-1被认为与骨骼维持有关。然而，NELL-1促骨形成作用的细胞决定因素仍不清楚。在此，我们在与临床相关的非人类灵长类动物腰椎融合模型中检测了重组人NELL-1（rhNELL-1）植入情况。使用磷灰石涂层的β-磷酸三钙载体实现了rhNELL-1蛋白的长期释放，导致干细胞抗原-1阳性（Sca-1+）间充质祖细胞（MPCs）局部流入，并在所有样本中实现了完全骨融合（脊柱融合率100%）。小鼠研究表明，Nell-1单倍体不足导致与低骨量相关的Sca-1+CD45-CD31-骨髓MPCs数量显著减少。相反，在小鼠中全身给予rhNELL-1显示出明显的合成代谢作用，同时Sca-1+CD45-CD31-骨髓MPCs数量增加。从机制上讲，rhNELL-1在MPCs中诱导Sca-1转录，这一过程需要完整的Wnt/β-连环蛋白信号传导。总之，NELL-1通过局部植入或静脉给药可有效诱导小型和大型动物模型中的骨形成。NELL-1诱导表达Sca-1的MPCs骨髓亚群扩增。这些发现为基于NELL-1的局部或全身骨形成治疗的临床转化提供了有力的依据。
