Activation of Nell-1 in BMSC Sheet Promotes Implant Osseointegration Through Regulating Runx2/Osterix Axis

Abstract

Neural epidermal growth factor-like 1 protein (Nell-1) is first studied because of its association with human craniosynostosis. Nell-1 has been used to accelerate the process of fracture healing because of the osteoinductive ability in recent years. However, the role of Nell-1 during the process of osteointegration is unknown. Here we show that activation of Nell-1 in the BMSC sheet promotes osseointegration in vivo and in vitro. We found that overexpression of Nell-1 improved osteogenic differentiation and enhanced matrix mineralization of BMSCs through increasing expression of Runx2 and Osterix. Activation of Nell-1 up-regulated the expression ratio of OPG/RANKL, which might have a negative influence on osteoclast differentiation. Furthermore, we obtained BMSC sheet-implant complexes transfected with lentivirus overexpressing and interfering Nell-1 in in vivo study, and confirmed that overexpression of Nell-1 promoted new bone formation around the implant and increased the bone-implant contacting area percentage. Our results demonstrate that activation of Nell-1 improves implant osteointegration by regulating Runx2/Osterix axis and shows the potential of BMSC sheet-implant complexes in gene therapy.

Runx2 and Nell-1 in dental follicle progenitor cells regulate bone remodeling and tooth eruption

“…As a novel, soluble growth factor with osteogenesis ability, Nell-1 can induce bone tissue denser, more calcified, and the positioning is more accurate compared with BMP-2 [106], indicating its biological advantages in the treatment of bone defects, and is a promising alternative to BMPs, attributable to its relative specificity to osteogenesis and less adverse effects. Nell-1 also improved implant osteointegration and showed the potential of Nell-1 gene therapy to shorten treatment time and broaden indications [80]. Besides being an important transcription factor in bone remodeling, Runx2 as a promising therapeutic target for cancers has become a research hotspot, since it plays a key role in the invasion and metastasis of cancers, and it is expected to become a new therapeutic target and contribute to the development of new drugs and the improvement of clinical efficacy [107].…”

“…The study also showed that instead of competing with Runx2 binding to the OSE2 sites, Osterix downregulated Nell-1 by affecting binding of RNA polymerase II to the Nell-1 promoter. Recent study [80] also showed that by means of regulating Runx2/Osterix axis, activation of Nell-1 significantly improved osseointegration. Through Nell-1 could be inhibited by Osterix, overexpression of Nell-1 rescued the interference of gene and protein levels of Osterix, and Nell-1 had positive feedback regulation on the expressions of Runx2 and Osterix (see Fig.…”

BMP-2 Delivery through Liposomes in Bone Regeneration

“…The Osx gene acts downstream from Runx2. Mice lacking Runx2 do not express Osx, but those missing Osx can have Runx2 intact, therefore, many consider Runx2 as the main gene in osteoblastic differentiation [36,37].…”

Crosstalk between Macrophages and Mesenchymal Stem Cells Regulated by Biomaterials and Its Role in Bone Regeneration

“…e presentation of growth factors, such as BMP-2, TGF-β1, and FGF2, to MSCs, has been found to target Runx2 and to activate and regulate osteogenesis [72][73][74]. In addition to proosteogenic effects, the supply of Nel-like protein type I (NELL-1) significantly reduced adipose differentiation of ADSCs while promoting osteogenic differentiation [75,76]. Moreover, the recently discovered transcriptional activator with PDZ-binding motif (TAZ) is another critical transcriptional modulator capable of stimulating osteogenesis while simultaneously blocking the differentiation of MSCs into adipocytes [77].…”