Inactivation of Nell-1 in Chondrocytes Significantly Impedes Appendicular Skeletogenesis.

NELL-1, an osteoinductive protein, has been shown to regulate skeletal ossification. Interestingly, an interstitial 11p14.1-p15.

Current development of biodegradable polymeric materials for biomedical applications.

In the last half-century, the development of biodegradable polymeric materials for biomedical applications has advanced significantly. Biodegradable polymeric materials are favored in the development of therapeutic devices, including temporary implants and three-dimensional scaffolds for tissue engineering. Further advancements have occurred in the utilization of biodegradable polymeric materials for pharmacological applications such as delivery vehicles for controlled/sustained drug release.

Upregulation of long noncoding RNA MEG3 inhibits the osteogenic differentiation of periodontal ligament cells.

Objective: This study aims to discuss long noncoding RNA (lncRNA) maternally expressed gene 3 (MEG3) function of regulating osteogenesis in human periodontal ligament cells (hPDLCs).

Methods: First, use of a mineralizing solution induced osteogenic differentiation of hPDLCs to establish a differentiated cell model. Through microarray analysis, we selected a lncRNA MEG3 with marked changes between differentiated and undifferentiated cells.

WNT16 induces proliferation and osteogenic differentiation of human perivascular stem cells.

Perivascular stem cells (PSC) are a progenitor population defined by their perivascular residence. Recent studies have examined the relative difference in Wnt ligands to induce PSC differentiation, including Wnt16. Here, we examine the role of Wnt16 in the proliferation and osteogenic differentiation of human PSC.

Vitamin D status contributes to the antimicrobial activity of macrophages against Mycobacterium leprae.

Background: The immune system depends on effector pathways to eliminate invading pathogens from the host in vivo. Macrophages (MΦ) of the innate immune system are armed with vitamin D-dependent antimicrobial responses to kill intracellular microbes. However, how the physiological levels of vitamin D during MΦ differentiation affect phenotype and function is unknown.

Frontal Bone Healing Is Sensitive to Wnt Signaling Inhibition via Lentiviral-Encoded Beta-Catenin Short Hairpin RNA.

The Wnt/β-catenin signaling pathway plays an integral role in skeletal biology, spanning from embryonic skeletal patterning through bone maintenance and bone repair. Most experimental methods to antagonize Wnt signaling in vivo are either systemic or transient, including genetic approaches, use of small-molecule inhibitors, or neutralizing antibodies. We sought to develop a novel, localized model of prolonged Wnt/β-catenin signaling blockade by the application and validation of a lentivirus encoding β-catenin short hairpin RNA (shRNA).

Neurexin Superfamily Cell Membrane Receptor Contactin-Associated Protein Like-4 (Cntnap4) Is Involved in Neural EGFL-Like 1 (Nell-1)-Responsive Osteogenesis.

Contactin-associated protein-like 4 (Cntnap4) is a member of the neurexin superfamily of transmembrane molecules that have critical functions in neuronal cell communication. Cntnap4 knockout mice display decreased presynaptic gamma-aminobutyric acid (GABA) and increased dopamine release that is associated with severe, highly penetrant, repetitive, and perseverative movements commonly found in human autism spectrum disorder patients. However, no known function of Cntnap4 has been revealed besides the nervous system.

MicroRNA-223 Suppresses Osteoblast Differentiation by Inhibiting DHRS3.

Background/aims: In this study, we aimed to use bioinformatics tools to identify the specific miRNAs and mRNAs involved in osteogenic differentiation and to further explore the way in which miRNA regulates osteogenic differentiation.

Methods: The microarray GSE80614, which includes data from 3 human mesenchymal stromal cells (hMSCs) and 3 hMSCs after 72 hours (hr) of osteogenic differentiation, was used to screen for differentially expressed mRNAs. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of these mRNAs were conducted using Gene Set Enrichment Analysis (GSEA).

Fibromodulin reduces scar size and increases scar tensile strength in normal and excessive-mechanical-loading porcine cutaneous wounds.

Hypertrophic scarring is a major postoperative complication which leads to severe disfigurement and dysfunction in patients and usually requires multiple surgical revisions due to its high recurrence rates. Excessive-mechanical-loading across wounds is an important initiator of hypertrophic scarring formation. In this study, we demonstrate that intradermal administration of a single extracellular matrix (ECM) molecule-fibromodulin (FMOD) protein-can significantly reduce scar size, increase tensile strength, and improve dermal collagen architecture organization in the normal and even excessive-mechanical-loading red Duroc pig wound models.

Nfatc1 Is a Functional Transcriptional Factor Mediating Nell-1-Induced Runx3 Upregulation in Chondrocytes.

Neural EGFL like 1 (Nell-1) is essential for chondrogenic differentiation, maturation, and regeneration. Our previous studies have demonstrated that Nell-1's pro-chondrogenic activities are predominantly reliant upon runt-related transcription factor 3 (Runx3)-mediated Indian hedgehog (Ihh) signaling. Here, we identify the nuclear factor of activated T-cells 1 (Nfatc1) as the key transcriptional factor mediating the Nell-1 → Runx3 signal transduction in chondrocytes.

The Effects of Systemic Therapy of PEGylated NEL-Like Protein 1 (NELL-1) on Fracture Healing in Mice.

Fractures are common, with an incidence of 13.7 per 1000 adults annually. Systemic agents have been widely used for enhancing bone regeneration; however, the efficacy of these therapeutics for the management and prevention of fracture remains unclear.

Fibromodulin reduces scar formation in adult cutaneous wounds by eliciting a fetal-like phenotype.

Blocking transforming growth factor (TGF)β1 signal transduction has been a central strategy for scar reduction; however, this approach appears to be minimally effective. Here, we show that fibromodulin (FMOD), a 59-kD small leucine-rich proteoglycan critical for normal collagen fibrillogenesis, significantly reduces scar formation while simultaneously increasing scar strength in both adult rodent models and porcine wounds, which simulate human cutaneous scar repair. Mechanistically, FMOD uncouples pro-migration/contraction cellular signals from pro-fibrotic signaling by selectively enhancing SMAD3-mediated signal transduction, while reducing AP-1-mediated TGFβ1 auto-induction and fibrotic extracellular matrix accumulation.

Neural EGFL-Like 1 Regulates Cartilage Maturation through Runt-Related Transcription Factor 3-Mediated Indian Hedgehog Signaling.

The pro-chondrogenic function of runt-related transcription factor 2 (Runx2) was previously considered to be dependent on direct binding with the promoter of Indian hedgehog (Ihh)-the major regulator of chondrocyte differentiation, proliferation, and maturation. The authors' previous studies identified neural EGFL like 1 (Nell-1) as a Runx2-responsive growth factor for chondrogenic differentiation and maturation. In this study, it was further revealed that the pro-chondrogenic activities of Nell-1 also rely on Ihh signaling, by showing: i) Nell-1 significantly elevated Ihh signal transduction; ii) Nell-1 deficiency markedly reduced Ihh activation in chondrocytes; and iii) Nell-1-stimulated chondrogenesis was significantly reduced by the specific hedgehog inhibitor cyclopamine.

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

NELL-1 is a secreted, osteogenic protein first discovered to control ossification of the cranial skeleton. Recently, NELL-1 has been implicated in bone maintenance. However, the cellular determinants of NELL-1's bone-forming effects are still unknown.

Isolation and characterization of canine perivascular stem/stromal cells for bone tissue engineering.

For over 15 years, human subcutaneous adipose tissue has been recognized as a rich source of tissue resident mesenchymal stem/stromal cells (MSC). The isolation of perivascular progenitor cells from human adipose tissue by a cell sorting strategy was first published in 2008. Since this time, the interest in using pericytes and related perivascular stem/stromal cell (PSC) populations for tissue engineering has significantly increased.

Combining Smoothened Agonist and NEL-Like Protein-1 Enhances Bone Healing.

Background: Nonhealing bone defects represent an immense biomedical burden. Despite recent advances in protein-based bone regeneration, safety concerns over bone morphogenetic protein-2 have prompted the search for alternative factors. Previously, the authors examined the additive/synergistic effects of hedgehog and Nel-like protein-1 (NELL-1) on the osteogenic differentiation of mesenchymal stem cells in vitro.

Fibromodulin Is Essential for Fetal-Type Scarless Cutaneous Wound Healing.

In contrast to adult and late-gestation fetal skin wounds, which heal with scar, early-gestation fetal skin wounds display a remarkable capacity to heal scarlessly. Although the underlying mechanism of this transition from fetal-type scarless healing to adult-type healing with scar has been actively investigated for decades, in utero restoration of scarless healing in late-gestation fetal wounds has not been reported. In this study, using loss- and gain-of-function rodent fetal wound models, we identified that fibromodulin (Fm) is essential for fetal-type scarless wound healing.

Calvarial Defect Healing Induced by Small Molecule Smoothened Agonist.

Hedgehog (Hh) signaling positively regulates both endochondral and intramembranous ossification. Use of small molecules for tissue engineering applications poses several advantages. In this study, we examined whether use of an acellular scaffold treated with the small molecule Smoothened agonist (SAG) could aid in critical-size mouse calvarial defect repair.

Polyelectrolyte Complex for Heparin Binding Domain Osteogenic Growth Factor Delivery.

During reconstructive bone surgeries, supraphysiological amounts of growth factors are empirically loaded onto scaffolds to promote successful bone fusion. Large doses of highly potent biological agents are required due to growth factor instability as a result of rapid enzymatic degradation as well as carrier inefficiencies in localizing sufficient amounts of growth factor at implant sites. Hence, strategies that prolong the stability of growth factors such as BMP-2/NELL-1, and control their release could actually lower their efficacious dose and thus reduce the need for larger doses during future bone regeneration surgeries.

Sclerostin expression in skeletal sarcomas.

Sclerostin (SOST) is an extracellular Wnt signaling antagonist which negatively regulates bone mass. Despite this, the expression and function of SOST in skeletal tumors remain poorly described. Here, we first describe the immunohistochemical staining pattern of SOST across benign and malignant skeletal tumors with bone or cartilage matrix (n=68 primary tumors).

Efficacy of Intraperitoneal Administration of PEGylated NELL-1 for Bone Formation.

Systemically delivered NEL-like molecule-1 (NELL-1), a potent pro-osteogenic protein, promotes bone formation in healthy and osteoporotic mouse models. PEGylation of NELL-1 (NELL-PEG) increases the half-life of the protein in a mouse model without compromising its osteogenic potential, thereby improving its pharmacokinetics upon systemic delivery. This study consists of a twofold approach: a biodistribution test and an in vivo osteogenic potential test.

The Rhoptry Pseudokinase ROP54 Modulates Toxoplasma gondii Virulence and Host GBP2 Loading.

Toxoplasma gondii uses unique secretory organelles called rhoptries to inject an array of effector proteins into the host cytoplasm that hijack host cell functions. We have discovered a novel rhoptry pseudokinase effector, ROP54, which is injected into the host cell upon invasion and traffics to the cytoplasmic face of the parasitophorous vacuole membrane (PVM). Disruption of ROP54 in a type II strain of T.

NELL-1 expression in tumors of cartilage.

Background/aims: NELL-1 is a novel osteochondral differentiation factor protein with increasing usage in tissue engineering. Previously, we reported the expression patterns of NELL-1 in bone-forming skeletal tumors. With increasing interest in the use of NELL-1 protein, we sought to examine the expression of NELL-1 in cartilage-forming tumors.

Prospective purification of perivascular presumptive mesenchymal stem cells from human adipose tissue: process optimization and cell population metrics across a large cohort of diverse demographics.

Background: Adipose tissue is an attractive source of mesenchymal stem cells (MSC) as it is largely dispensable and readily accessible through minimally invasive procedures such as liposuction. Until recently MSC could only be isolated in a process involving ex-vivo culture and their in-vivo identity, location and frequency remained elusive. We have documented that pericytes (CD45-, CD146+, and CD34-) and adventitial cells (CD45-, CD146-, CD34+) (collectively termed perivascular stem cells or PSC) represent native ancestors of the MSC, and can be prospectively purified using fluorescence activated cell sorting (FACS).