Calvarial Cleidocraniodysplasia-Like Defects With ENU-Induced Nell-1 Deficiency

Abstract

NELL-1, first identified by its overexpression in synostotic cranial sutures, is a novel osteoinductive growth and differentiation factor. In order to further define Nell-1’s role in craniofacial patterning, we characterized defects of the ENU-induced Nell-1 deficient (END) mice, focusing on both intramembranous and endochondral cranial bones. Results showed that calvarial bones of neonatal END mice were reduced in thickness and density, with a phenotype resembling calvarial cleidocraniodysplasia (CCD). In addition, a global reduction in osteoblast markers was observed, including reductions in Runx2, alkaline phosphatase, and osteocalcin. Remarkably, detailed analysis of endochondral bones showed dysplasia as well. The chondrocranium in the END mouse showed enrichment for early, proliferating Sox9+ chondrocytes, while in contrast markers of chondrocytes maturation were reduced. These data suggest that Nell-1 is an important growth factor for regulation of osteochondral differentiation, by regulating both Runx2 and Sox9 expression within the calvarium. In summary, Nell-1 is required for normal craniofacial membranous and endochondral skeletal development.

Additive Effects of Sonic Hedgehog and Nell-1 Signaling in Osteogenic Versus Adipogenic Differentiation of Human Adipose-Derived Stromal Cells

“…Loss of Ihh in the mouse (Ihh null animals) results in a global reduction in expanse, thickness, and degree of mineralization of intramembranous cranial bones [17]. Interestingly, loss of function of Nell-1 in the mouse results in a strikingly similar calvarial phenotype with reduced bone thickness and increased sutural width due to defective mineralization [46]. These loss-of-function experiments suggest partially overlapping roles for both Hedgehog and Nell-1 signaling in intramembranous bone ossification.…”

Human Perivascular Stem Cells Show Enhanced Osteogenesis and Vasculogenesis with Nel-Like Molecule I Protein

“…37 Studies involving overand under-expression of NELL-1 in mice have yielded craniosynostotic and craniodysplastic defects, respectively. 38,39 Significant steps have already been made toward the use of recombinant NELL-1 for bone tissue engineering purposes. For example, prior studies in the rat intertransverse lumbar spine fusion 29 and sheep intrabody lumbar spine fusion 40 have shown a significant efficacy in the rate of fusion and degree of bone formation.…”

Human NELL1 Protein Augments Constructive Tissue Remodeling with Biologic Scaffolds

“…Previous attempts at developing tissue-engineered skeletal muscle implants have failed to address vascularization or innervation of the constructs [Dennis and Kosnik, 2000;Borschel et al, 2004;du Moon et al, 2008]. In the present study, as skeletal muscle tissue formed in situ within the initially acellular construct, a complex neurovascular bed formed alongside the NELL1 has been shown to regulate expression of ECM components in other musculoskeletal tissues, including bone and cartilage [Desai et al, 2006;Lee et al, 2010;Zhang et al, 2012]. Numerous small and large animal studies in bone and cartilage regeneration showed the activity of NELL1 in producing new tissue of high architectural and functional quality [Aghaloo et al, 2007;Aghaloo et al, 2010;Li et al, 2011;Xue et al, 2011;Siu et al, 2012].…”

“…NELL1 is also expressed in many soft tissues, including intestine, brain and kidney, suggesting a role in soft tissue morphostasis [Franke et al, 2007]. Furthermore, NELL1 is essential for the production of ECM components such as collagens, proteoglycans and tenascins [Desai et al, 2006;Lee et al, 2010;Zhang et al, 2012]. However, to date, the role of NELL1 in soft tissue injuries has not been investigated.…”