Nell-1 Is a Key Functional Modulator in Osteochondrogenesis and Beyond

Abstract

Neural EGFL-like 1 (Nell-1) is a well-studied osteogenic factor that has comparable osteogenic potency with the Food and Drug Administration–approved bone morphogenic protein 2 (BMP-2). In this review, which aims to summarize the advanced Nell-1 research in the past 10 y, we start with the correlation of structural and functional relevance of the Nell-1 protein with the identification of a specific receptor of Nell-1, contactin-associated protein-like 4 (Cntnap4), for osteogenesis. The indispensable role of Nell-1 in normal craniofacial and appendicular skeletal development and growth was also defined by using the newly developed tissue-specific Nell-1 knockout mouse lines in addition to the existing transgenic mouse models. With the achievements on Nell-1’s osteogenic therapeutic evaluations from multiple preclinical animal models for local and systemic bone regeneration, the synergistic effect of Nell-1 with BMP-2 on osteogenesis, as well as the advantages of Nell-1 as an osteogenic protein with antiadipogenic, anti-inflammatory, and provascularized characteristics over BMP-2 in bone tissue engineering, is highlighted, which lays the groundwork for the clinical trial approval of Nell-1. At the molecular level, besides the mitogen-activated protein kinase (MAPK) signaling pathway, we emphasize the significant involvement of the Wnt/β-catenin pathway as well as the key regulatory molecules Runt-related transcription factor 2 (Runx2) in Nell-1-induced osteogenesis. In addition, the involvement of Nell-1 in chondrogenesis and its relevant pathologies have been revealed with the participation of the nuclear factor of activated T cells 1 (Nfatc1), Runx3, and Indian hedgehog (Ihh) signaling pathways, although the mechanistic insights of Nell-1’s osteochondrogenic property will be continuously evolving. With this perspective, we elucidate some emerging and novel functional properties of Nell-1 in oral-dental and neural tissues that will be the frontiers of future Nell-1 studies beyond the context of bone and cartilage. As such, the therapeutic potential of Nell-1 continues to evolve and grow with continuous pursuit.

Advances in Membranous Nephropathy

“…NELL-1 is a secreted, 90-kDa protein expressed in osteoblasts and promoting bone regeneration [ 53 ]. While it is overexpressed in patients with craniosynostosis, its expression in the kidney is weak and it is virtually absent from podocytes except in pathological conditions such as PLA2R-related MN.…”

NELL-1 Increased the Osteogenic Differentiation and mRNA Expression of Spheroids Composed of Stem Cells

“…NELL-1 can be widely applied in oral and maxillofacial regions due to its effects on bone and cartilage [24]. NELL-1 enhanced osteogenic differentiation of osteoblast-like cells cultured on the surface of titanium [25].…”

“…NELL-1 is reported to bind to integrin β1, leading to the induction of the Wnt/β-catenin signaling pathway [5]. NELL-1 produced comparable osteogenic potency with bone morphogenic protein-2, which is approved by the Food and Drug Administration [24]. However, NELL-1 is shown to enhance bone defect healing through recruitment of endogenous cells and induction of vascularization, which may differ from the mechanism of bone morphogenetic protein-2 [15].…”

Mechanisms of Primary Membranous Nephropathy

“…The association of NELL-1 MN with cancer is in accordance with NELL-1 being a potent growth factor for the osteochondral lineage [ 118 ]. NELL-1 activates the mitogen-activated protein kinase (MAPK) pathway and Wnt/β-catenin signaling [ 119 ]; both are well-established oncogenic events [ 120 , 121 ].…”

“…Nonetheless, the authors favored the possibility of NELL-1 shedding from the podocyte for the immune complex deposition along the GBM [ 115 ]. NELL-1 is a secreted protein [ 118 ]. With NELL-1 being expressed at higher levels in other tissues, together with its presence in the extracellular domain (secreted), and the circulating anti-NELL-1 antibody in MN patients, the possibility of the deposition of the anti-NELL-1-Ab-NELL-1 complex into to the subepithelial region cannot be excluded.…”