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

James, Aaron W.; Shen, Jia; Tsuei, Rebecca; Nguyen, Alan; Khadarian, Kevork; Meyers, Carolyn A.; Pan, Hsin Chuan; Li, Weiming; Kwak, Jin Hee; Asatrian, Greg; Culiat, Cymbeline T.; Lee, Min; Ting, Kang; Zhang, Xinli

doi:10.1172/jci.insight.92573

Cited by 21 publications

(23 citation statements)

References 45 publications

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“…James et al[20] investigated the effects of NELL-1 on spinal fusion in a 5- to 7-year-old Rhesus macaque posterolateral lumbar (L3-L4 and L5-L6) model. Three groups were studied: intervertebral cage plus DBX mixed with saline- or rh-NELL-1-(1.0 or 1.7 mg/mL) loaded apatite-coated β-tricalcium phosphate (aTCP) particles.…”

Section: Resultsmentioning

confidence: 99%

Investigational growth factors utilized in animal models of spinal fusion: Systematic review

Cottrill¹,

Ahmed²,

Lessing³

et al. 2019

WJO

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BACKGROUND Over 400000 Americans annually undergo spinal fusion surgeries, yet up to 40% of these procedures result in pseudoarthrosis even with iliac crest autograft, the current “gold standard” treatment. Tissue engineering has the potential to solve this problem via the creation of bone grafts involving bone-promoting growth factors ( e.g ., bone morphogenetic protein 2). A broad assessment of experimental growth factors is important to inform future work and clinical potential in this area. To date, however, no study has systematically reviewed the investigational growth factors utilized in preclinical animal models of spinal fusion. AIM To review all published studies assessing investigational growth factors for spinal fusion in animal models and identify promising agents for translation. METHODS We conducted a systematic review of the literature using PubMed, Embase, Cochrane Library, and Web of Science databases with searches run on May 29 th , 2018. The search query was designed to include all non-human, preclinical animal models of spinal fusion reported in the literature without a timespan limit. Extracted data for each model included surgical approach, level of fusion, animal species and breed, animal age and sex, and any other relevant characteristics. The dosages/sizes of all implant materials, spinal fusion rates, and follow-up time points were recorded. The data were analyzed and the results reported in tables and text. PRISMA guidelines were followed for this systematic review. RESULTS Twenty-six articles were included in this study, comprising 14 experimental growth factors: AB204 ( n = 1); angiopoietin 1 ( n = 1); calcitonin ( n = 3); erythropoietin ( n = 1); basic fibroblast growth factor ( n = 1); growth differentiation factor 5 ( n = 4), combined insulin-like growth factor 1 + transforming growth factor beta ( n = 4); insulin ( n = 1); NELL-1 ( n = 5); noggin ( n = 1); P-15 ( n = 1); peptide B2A ( n = 2); and secreted phosphoprotein 24 ( n = 1). The fusion rates of the current gold standard treatment (autologous iliac crest bone graft, ICBG) and the leading clinically used growth factor (BMP-2) ranged widely in the included studies, from 0-100% for ICBG and from 13%-100% for BMP-2. Among the identified growth factors, calcitonin, GDF-5, NELL-1, and P-15 resulted in fusion rates of 100% in some cases. In addition, six growth factors - AB204, angiopoietin 1, GDF-5, insulin, NELL-1, and peptide B2A - resulted in significantly enhanced fusion rates compared to ICBG, BMP...

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Section: Resultsmentioning

confidence: 99%

Investigational growth factors utilized in animal models of spinal fusion: Systematic review

Cottrill¹,

Ahmed²,

Lessing³

et al. 2019

WJO

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“…In our recent study, we observed that Nell-1 signaling increases Sca-1 + MSC numbers across multiple orthopaedic models, including MSC culture, murine long bone injection, murine systemic administration, and non-human primate spinal fusion. 21 In this study, the long isoform of NELL-1 was used only. Overall, it is not clear the extent to which this expansion in Sca-1+ MSC numbers has a clear correlate to the increase in cell proliferation observed in cell culture in the current studies.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, the mitogenic effects of NELL-1 protein are modest and it is unclear if this alone underlies the significant changes in Sca-1 + cell numbers observed in our prior study. 21 Overall, NELL-1 possesses several theoretical benefits as a potential bone-forming therapy. NELL-1 has documented tumor suppressive properties and its expression is lost in several malignant epithelial tumors.…”

Section: Discussionmentioning

confidence: 99%

Age dependent effects of NELL-1 isoforms on bone marrow stromal cells

Meyers

Sun

Chang

et al. 2019

Journal of Orthopaedics

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NELL-1 is an osteogenic protein first discovered to control ossification of the cranium. NELL-1 exists in at least two isoforms. The full-length NELL-1 contains 810 amino acid (aa) (NELL-1810), the N-terminal-truncated NELL-1 isoform contains 570 aa (NELL-1570). The differences in cellular effects between NELL-1 isoforms are not well understood. Methods: Here, BMSC were derived from adult or aged mice, followed by overexpression of NELL-1810 or NELL-1570. Cell morphology, proliferation, and gene expression were examined. Results/Conclusions: Overall, the proliferative effect of NELL-1570 was age dependent, showing prominent induction in adult but not aged mice.

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“…At 3 years and 7 months of age, her height was 83.8 cm, far below average (–3.5 SD). Besides these studies implicating the Nell‐1 gene with various phenotypes, our previous studies have also shown that Nell‐1 holds promising therapeutic potential in the regeneration of bone and cartilage as revealed in numerous preclinical animal models with Nell‐1 application ranging from rodents to non‐human primates . Therefore, Nell‐1 is among the functional key factors in modulating skeletogenesis and warrants further in‐depth mechanistic research.…”

Section: Introductionmentioning

confidence: 89%

“…Besides these studies implicating the Nell-1 gene with various phenotypes, our previous studies have also shown that Nell-1 holds promising therapeutic potential in the regeneration of bone and cartilage as revealed in numerous preclinical animal models with Nell-1 application ranging from rodents to non-human primates. (6)(7)(8)(9)(10)(11) Therefore, Nell-1 is among the functional key factors in modulating skeletogenesis and warrants further in-depth mechanistic research. However, a homozygous ENU-induced point mutation in the mouse Nell-1 gene results in neonatal death.…”

Section: Introductionmentioning

confidence: 99%

Inactivation of Nell-1 in Chondrocytes Significantly Impedes Appendicular Skeletogenesis

Kim

et al. 2018

Journal of Bone and Mineral Research

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NELL‐1, an osteoinductive protein, has been shown to regulate skeletal ossification. Interestingly, an interstitial 11p14.1‐p15.3 deletion involving the Nell‐1 gene was recently reported in a patient with short stature and delayed fontanelle closure. Here we sought to define the role of Nell‐1 in endochondral ossification by investigating Nell‐1‐specific inactivation in Col2α1‐expressing cell lineages. Nell‐1flox/flox; Col2α1‐Cre+ (Nell‐1Col2α1KO) mice were generated for comprehensive analysis. Nell‐1Col2α1KO mice were born alive but displayed subtle femoral length shortening. At 1 and 3 months postpartum, Nell‐1 inactivation resulted in dwarfism and premature osteoporotic phenotypes. Specifically, Nell‐1Col2α1KO femurs and tibias exhibited significantly reduced length, bone mineral density (BMD), bone volume per tissue volume (BV/TV), trabecular number/thickness, cortical volume/thickness/density, and increased trabecular separation. The decreased bone formation rate revealed by dynamic histomorphometry was associated with altered numbers and/or function of osteoblasts and osteoclasts. Furthermore, longitudinal observations by in vivo micro‐CT showed delayed and reduced mineralization at secondary ossification centers in mutants. Histologically, reduced staining intensities of Safranin O, Col‐2, Col‐10, and fewer BrdU‐positive chondrocytes were observed in thinner Nell‐1Col2α1KO epiphyseal plates along with altered distribution and weaker expression level of Ihh, Patched‐1, PTHrP, and PTHrP receptor. Primary Nell‐1Col2α1KO chondrocytes also exhibited decreased proliferation and differentiation, and its downregulated expression of the Ihh‐PTHrP signaling molecules can be partially rescued by exogenous Nell‐1 protein. Moreover, intranuclear Gli‐1 protein and gene expression of the Gli‐1 downstream target genes, Hip‐1 and N‐Myc, were also significantly decreased with Nell‐1 inactivation. Notably, the rescue effects were diminished/reduced with application of Ihh signaling inhibitors, cyclopamine or GANT61. Taken together, these findings suggest that Nell‐1 is a pivotal modulator of epiphyseal homeostasis and endochondral ossification. The cumulative chondrocyte‐specific Nell‐1 inactivation significantly impedes appendicular skeletogenesis resulting in dwarfism and premature osteoporosis through inhibiting Ihh signaling and predominantly altering the Ihh‐PTHrP feedback loop. © 2018 American Society for Bone and Mineral Research.

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

Cited by 21 publications

References 45 publications

Investigational growth factors utilized in animal models of spinal fusion: Systematic review

Investigational growth factors utilized in animal models of spinal fusion: Systematic review

Age dependent effects of NELL-1 isoforms on bone marrow stromal cells

Inactivation of Nell-1 in Chondrocytes Significantly Impedes Appendicular Skeletogenesis

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