The NELL-1 protein contains combination of chordin-like, cysteine rich domans, NH2-termianl thrombospondin-like module, and EGF-like repeats. Human NELL-1 shares a 93% homology to its rat ortholog. Rat Nell-1 had been shown to be expressed in rat calvarial osteoprogenitor cells but largely absent in rat tibia, stromal cell, and fibroblast cell culture. Transgenic mice carrying an over-expressed human NELL-1 exhibited a similar phenotype to the pathological features resembled in CS patients, e.g., prematurely closing sutures and thickened, overgrown ridges of calvarial ridges with closing/overlapping osteogenic fronts.

The effects of Nell-1 expression had been observed to be skeletal specific especially in the cranium specific. This may explain why the transgenic bearing Nell-1 over-expression exhibits more resemblance to CS skeletal pathological features than those having other candidate genes identified in familial CS patients. These genes may play important roles in osteoblast proliferation and differentiation, they have more generalized roles during embryogenesis and their over-expression may induce other pathways in development.

Over-expression of Nell-1 in vitro had been observed to induce mineralization, as indicated by an increase in Alkaline Phosphatase activity (ALP) and an up-regulation of late differentiation markers such as Bmp7, osteopontin, and osteocalcin. Furthermore, researchers tested the downstream effect of down-regulating Nell-1 by using antisense Nell-1. Results indicated reduced ALP activity in addition to a down regulation of osteocalcin and osteopontin RNA expression.

Experiment in comparing the activity of NELL-1 protein with that of BMP4 was conducted using an ALP activity assay. Functional NELL-1 proteins from culture medium were added to osteoblast cultures and displayed a 1000-fold difference with respect to BMP-4. The osteogenic activity of NELL-1 therefore may be applied in osteoporosis, tissue engineering, and regeneration, distraction osteogenesis, and dental implant and periodontal bone defects.

Related Papers (Selected) Craniosynostosis in transgenic mice overexpressing Nell-1. J Clin Invest. 2002 Sep;110(6):861-70.more... Biochemical characterization and expression analysis of neural thrombospondin-1-like proteins NELL1 and NELL2. Biochem Biophys Res Commun. 1999 Nov;265(1):79-86.more... Human NELL-1 expressed in unilateral coronal synostosis. J Bone Miner Res. 1999 Jan;14(1):80-9.more...

Reference: UCLA Case No. 1999-560

US Patent No.: 7,052,856