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Although headgear is rarely used in adult patients, its use in adults is mainly for anchorage control. In the current case report, a 24-year-old patient had a skeletal Class I relationship with a Class II tendency, brachyfacial pattern, significant facial asymmetry, and dental 3/4 cusp Class II molar and canine relationships on both sides. The patient declined surgery, and facial asymmetry was not his concern. The final treatment goal was to achieve a stable Class I dental relationship and normal occlusion without significantly compromising the patient's profile. The patient was compliant with the use of cervical-pull headgear after he refused the options of orthodontic-orthognathic combined treatment, maxillary premolar extraction, or temporary skeletal anchorage mini-implants. A 5-mm maxillary arch distal movement was accomplished without significant distal tipping of the molar crowns. The active treatment duration was 31 months. Proper overbite and overjet, balanced occlusion, and an acceptable facial profile were achieved. The treatment results inspire reconsideration of the possibility of using headgear in dental Class II correction in adult patients.

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. Meanwhile, secretory protein neural EGFL-like 1 (Nell-1) is known to exert potent osteogenic effects in multiple small and large animal models without the off-target effects commonly found with bone morphogenetic protein 2. In this study, while searching for a Nell-1-specific cell surface receptor during osteogenesis, we identified and validated a ligand/receptor-like interaction between Nell-1 and Cntnap4 by demonstrating: 1) Nell-1 and Cntnap4 colocalization on the surface of osteogenic-committed cells; 2) high-affinity interaction between Nell-1 and Cntnap4; 3) abrogation of Nell-1-responsive Wnt and MAPK signaling transduction, as well as osteogenic effects, via Cntnap4 knockdown; and 4) replication of calvarial cleidocranial dysplasias-like defects observed in Nell-1-deficient mice in Wnt1-Cre-mediated Cntnap4-knockout transgenic mice. In aggregate, these findings indicate that Cntnap4 plays a critical role in Nell-1-responsive osteogenesis. Further, this is the first functional annotation for Cntnap4 in the musculoskeletal system. Intriguingly, Nell-1 and Cntnap4 also colocalize on the surface of human hippocampal interneurons, implicating Nell-1 as a potential novel ligand for Cntnap4 in the nervous system. This unexpected characterization of the ligand/receptor-like interaction between Nell-1 and Cntnap4 indicates a novel biological functional axis for Nell-1 and Cntnap4 in osteogenesis and, potentially, in neural development and function. © 2018 American Society for Bone and Mineral Research.

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. Since pig skin is recognized by the Food and Drug Administration as the closest animal equivalent to human skin, and because red Duroc pigs show scarring that closely resembles human proliferative scarring and hypertrophic scarring, FMOD‐based technologies hold high translational potential and applicability to human patients suffering from scarring—especially hypertrophic scarring.

Arthritis, an inflammatory condition that causes pain and cartilage destruction in joints, affects over 54.4 million people in the US alone. Here, for the first time, we demonstrated the emerging role of Neural EGFL like 1 (NELL-1) in arthritis pathogenesis by showing that Nell-1- haploinsufficient (Nell-1(+/6R)) mice had accelerated and aggravated osteoarthritis progression with elevated inflammatory markers in both spontaneous primary osteoarthritis (OA) and chemical-induced secondary OA models. In the chemical-induced OA model, intra-articular injection of interleukin (IL)1β induced more severe inflammation and cartilage degradation in the knee joints of Nell-1(+/6R) mice than in wildtype animals. Mechanistically, in addition to its pro-chondrogenic potency, NELL-1 also effectively suppressed the expression of inflammatory cytokines and their downstream cartilage catabolic enzymes by upregulating runt-related transcription factor (RUNX)1 in mouse and human articular cartilage chondrocytes. Notably, NELL-1 significantly reduced IL1b-stimulated inflammation and damage to articular cartilage in vivo. In particular, NELL-1 administration markedly reduced the symptoms of antalgic gait observed in IL1β-challenged Nell-1(+/6R) mice. Therefore, NELL-1 is a promising pro-chondrogenic, anti-inflammatory dual-functional disease-modifying osteoarthritis drug (DMOAD) candidate for preventing and suppressing arthritis-related cartilage damage.

Tumorigenicity is a well-documented risk to overcome for pluripotent or multipotent cell applications in regenerative medicine. To address the emerging demand for safe cell sources in tissue regeneration, we established a novel, protein-based reprogramming method that does not require genome integration or oncogene activation to yield multipotent fibromodulin (FMOD)-reprogrammed (FReP) cells from dermal fibroblasts. When compared with induced pluripotent stem cells (iPSCs), FReP cells exhibited a superior capability for bone and skeletal muscle regeneration with markedly less tumorigenic risk. Moreover, we showed that the decreased tumorigenicity of FReP cells was directly related to an upregulation of cyclin-dependent kinase inhibitor 2B (CDKN2B) expression during the FMOD reprogramming process. Indeed, sustained suppression of CDKN2B resulted in tumorigenic, pluripotent FReP cells that formed teratomas in vivo that were indistinguishable from iPSC-derived teratomas. These results highlight the pivotal role of CDKN2B in cell fate determination and tumorigenic regulation and reveal an alternative pluripotent/multipotent cell reprogramming strategy that solely uses FMOD protein.

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. Consequently, FMOD accelerates TGFβ1-responsive adult fibroblast migration, myofibroblast conversion, and function. Furthermore, our findings strongly indicate that, by delicately orchestrating TGFβ1 activities rather than indiscriminately blocking TGFβ1, FMOD elicits fetal-like cellular and molecular phenotypes in adult dermal fibroblasts in vitro and adult cutaneous wounds in vivo, which is a unique response of living system undescribed previously. Taken together, this study illuminates the signal modulating activities of FMOD beyond its structural support functions, and highlights the potential for FMOD-based therapies to be used in cutaneous wound repair.

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. Importantly, the authors demonstrated that Nell-1–responsive Ihh signaling and chondrogenic differentiation extended to Runx2−/− models in vitro and in vivo. In Runx2−/− chondrocytes, Nell-1 stimulated the expression and signal transduction of Runx3, another transcription factor required for complete chondrogenic differentiation and maturation. Furthermore, knocking down Runx3 in Runx2−/− chondrocytes abolished Nell-1's stimulation of Ihh-associated molecule expression, which validates Runx3 as a major mediator of Nell-1–stimulated Ihh activation. For the first time, the Runx2→Nell-1→Runx3→Ihh signaling cascade during chondrogenic differentiation and maturation has been identified as an alternative, but critical, pathway for Runx2 to function as a pro-chondrogenic molecule via Nell-1.

The periodontal ligament (PDL) is a group of highly aligned and organized connective tissue fibers that intervenes between the root surface and the alveolar bone. The unique architecture is essential for the specific physiological functionalities of periodontium. The regeneration of periodontium has been extensively studied by researchers, but very few of them pay attention to the alignment of PDL fibers as well as its functionalities. In this study, we fabricated a three-dimensional multilayered scaffold by embedding highly aligned biodegradable poly (e-caprolactone)-poly(ethylene glycol) (PCE) copolymer electrospun nanofibrous mats into porous chitosan (CHI) to provide topographic cues and guide the oriented regeneration of periodontal tissue. In vitro , compared with random group and porous control, aligned nanofibers embedded scaffold could guide oriented arrangement and elongation of cells with promoted infiltration, viability and increased periodontal ligament-related genes expression. In vivo , aligned nanofibers embedded scaffold showed more organized arrangement of regenerated PDL nearly perpendicular against the root surface with more extensive formation of mature collagen fibers than random group and porous control. Moreover, higher expression level of periostin and more significant formation of tooth-supporting mineralized tissue were presented in the regenerated periodontium of aligned scaffold group. Incorporation of aligned PCE nanofibers into porous CHI proved to be applicable for oriented regeneration of periodontium, which might be further utilized in regeneration of a wide variety of human tissues with a specialized direction. Statement of Significance The regeneration of periodontium has been extensively studied by researchers, but very few of them give attention to the alignment of periodontal ligament (PDL) fibers as well as its functionalities. The key issue is to provide guidance to the orientation of cells with aligned arrangement of collagen fibers perpendicular against the root surface. This study aimed to promote oriented regeneration of periodontium by structural mimicking of scaffolds. The in vitro and in vivo performances of the scaffolds were further evaluated to test the topographic-guiding and periodontium healing potentials. We also think our research may provide ideas in regeneration of a wide variety of human tissues with a specialized direction.