TY - JOUR
T1 - NELL-1 induces Sca-1+ mesenchymal progenitor cell expansion in models of bone maintenance and repair
AU - James, Aaron W.
AU - Shen, Jia
AU - Tsuei, Rebecca
AU - Nguyen, Alan
AU - Khadarian, Kevork
AU - Meyers, Carolyn A.
AU - Pan, Hsin Chuan
AU - Li, Weiming
AU - Kwak, Jin H.
AU - Asatrian, Greg
AU - Culiat, Cymbeline T.
AU - Lee, Min
AU - Ting, Kang
AU - Zhang, Xinli
AU - Soo, Chia
N1 - Funding Information:
The present work was supported by the NIH/National Institute of Arthritis and Musculoskeletal and Skin (grant numbers R01 AR061399, R01 AR066782, and K08 AR068316), and the Orthopaedic Research and Education Foundation with funding provided by the Musculoskeletal Transplant Foundation.
Funding Information:
We would like to thank the following individuals and offices for their expertise: TPCL and Surgical Pathology divisions of the UCLA Department of Pathology and Laboratory Medicine. We thank Michael Chiang and Janette Zara for their excellent technical assistance. The authors thank Arthur A. Gertzman for the donation of demineralized bone graft products, and for his lifetime contributions to the field. The present work was supported by the NIH/National Institute of Arthritis and Musculoskeletal and Skin (grant numbers R01 AR061399, R01 AR066782, and K08 AR068316), and the Orthopaedic Research and Education Foundation with funding provided by the Musculoskeletal Transplant Foundation.
Publisher Copyright:
© 2017 American Society for Clinical Investigation. All rights reserved.
PY - 2017/6/15
Y1 - 2017/6/15
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.92573
DO - 10.1172/jci.insight.92573
M3 - Article
C2 - 28614787
AN - SCOPUS:85042302346
SN - 0021-9738
VL - 2
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 12
M1 - e92573
ER -