Novel wnt regulator NEL-like molecule-1 antagonizes adipogenesis and augments osteogenesis induced by bone morphogenetic protein 2

Jia Shen, Aaron W. James, Xinli Zhang, Shen Pang, Janette N. Zara, Greg Asatrian, Michael Chiang, Min Lee, Kevork Khadarian, Alan Nguyen, Kevin S. Lee, Ronald K. Siu, Sotirios Tetradis, Kang Ting, Chia Soo

Research output: Contribution to journalArticlepeer-review

Abstract

The differentiation factor NEL-like molecule-1 (NELL-1) has been reported as osteoinductive in multiple in vivo preclinical models. Bone morphogenetic protein (BMP)-2 is used clinically for skeletal repair, but in vivo administration can induce abnormal, adipose-filled, poor-quality bone. We demonstrate that NELL-1 combined with BMP2 significantly optimizes osteogenesis in a rodent femoral segmental defect model by minimizing the formation of BMP2-induced adipose-filled cystlike bone. In vitro studies using the mouse bone marrow stromal cell line M2-10B4 and human primary bone marrow stromal cells have confirmed that NELL-1 enhances BMP2-induced osteogenesis and inhibits BMP2-induced adipogenesis. Importantly, the ability of NELL-1 to direct BMP2-treated cells toward osteogenesis and away from adipogenesis requires intact canonical Wnt signaling. Overall, these studies establish the feasibility of combining NELL-1 with BMP2 to improve clinical bone regeneration and provide mechanistic insight into canonical Wnt pathway activity during NELL-1 and BMP2 osteogenesis. The novel abilities of NELL-1 to stimulate Wnt signaling and to repress adipogenesis may highlight new treatment approaches for bone loss in osteoporosis.

Original languageEnglish (US)
Pages (from-to)419-434
Number of pages16
JournalAmerican Journal of Pathology
Volume186
Issue number2
DOIs
StatePublished - Feb 1 2016

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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