Nell-1 Protein Promotes Bone Formation in a Sheep Spinal Fusion Model

Abstract

Bone morphogenetic proteins (BMPs) are widely used as bone graft substitutes in spinal fusion, but are associated with numerous adverse effects. The growth factor Nel-like molecule-1 (Nell-1) is mechanistically distinct from BMPs and can minimize complications associated with BMP therapies. This study evaluates the efficacy of Nell-1 combined with demineralized bone matrix (DBM) as a novel bone graft material for interbody spine fusion using sheep, a phylogenetically advanced animal with biomechanical similarities to human spine. Nell-1 + sheep DBM or Nell-1 + heat-inactivated DBM (inDBM) (to determine the osteogenic effect of residual growth factors in DBM) were implanted in surgical sites as follows: (1) DBM only (control) (n = 8); (2) DBM + 0.3 mg/mL Nell-1 (n = 8); (3) DBM + 0.6 mg/mL Nell-1 (n = 8); (4) inDBM only (control) (n = 4); (5) inDBM + 0.3 mg/mL Nell-1 (n = 4); (6) inDBM + 0.6 mg/mL Nell-1 (n = 4). Fusion was assessed by computed tomography, microcomputed tomography, and histology. One hundred percent fusion was achieved by 3 months in the DBM + 0.6 mg/mL Nell-1 group and by 4 months in the inDBM + 0.6 mg/mL Nell-1 group; bone volume and mineral density were increased by 58% and 47%, respectively. These fusion rates are comparable to published reports on BMP-2 or autograft bone efficacy in sheep. Nell-1 is an independently potent osteogenic molecule that is efficacious and easily applied when combined with DBM.

Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2

“…10 In translational models of bone repair, exogenous NELL-1 induces potent osseous healing of critical-sized rat calvarial defects, 11 repair of rat femoral segmental defects (FSDs), 12 as well as successful spinal fusion in rats 13,14 and sheep. 15 Based on these results demonstrating reproducible preclinical osteoinductivity in multiple small and large animal models, NELL-1 is being developed for therapeutic use in spinal fusion in humans.…”

NELL-1 induces Sca-1+ mesenchymal progenitor cell expansion in models of bone maintenance and repair

“…Mechanistically, NELL-1 binds to the cell surface heterodimer integrin α3β1 (13), resulting in several intracellular signaling changes that induce osteoblastogenic programming, including focal adhesion kinase (FAK) phosphorylation (14), increased mitogen-activated protein kinase (MAPK) signaling activity (15)(16)(17), and increased Wnt/β-catenin signaling activity (4,18). Despite the well-demonstrated pro-osteogenic effects of NELL-1 (19)(20)(21)(22)(23), there has been little understanding of the cellular mediators of its effects, nor the role of NELL-1 in the maintenance or expansion of MPC pools.…”

NELL-1 expression in tumors of cartilage

“…[1][2][3][4][5] NELL-1 is a secreted protein of 810-amino acids with a molecular weight of about 90 kDa before N-glycosylation and oligomerization. 6 NELL-1 was first identified to have bone-forming properties by its overexpression in fusing cranial sutures.…”