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3D printing enables the creation of scaffolds with precisely controlled morphometric properties for multiple tissue types, including musculoskeletal tissues such as cartilage and bone. Computed tomography (CT) imaging has been combined with 3D printing to fabricate anatomically scaled patient-specific scaffolds for bone regeneration. However, anatomically scaled scaffolds typically lack sufficient resolution to recapitulate the <100 micrometer-scale trabecular architecture essential for investigating the cellular response to the morphometric properties of bone. In this study, it is hypothesized that the architecture of trabecular bone regulates osteoblast differentiation and mineralization. To test this hypothesis, human bone-templated 3D constructs are fabricated via a new micro-CT/3D inkjet printing process. It is shown that this process reproducibly fabricates bone-templated constructs that recapitulate the anatomic site-specific morphometric properties of trabecular bone. A significant correlation is observed between the structure model index (a morphometric parameter related to surface curvature) and the degree of mineralization of human mesenchymal stem cells, with more concave surfaces promoting more extensive osteoblast differentiation and mineralization compared to predominately convex surfaces. These findings highlight the significant effects of trabecular architecture on osteoblast function.
© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Cranial neural crest cells are a multipotent cell population that generate all the elements of the pharyngeal cartilage with differentiation into chondrocytes tightly regulated by temporal intracellular and extracellular cues. Here, we demonstrate a novel role for miR-27, a highly enriched microRNA in the pharyngeal arches, as a positive regulator of chondrogenesis. Knock down of miR-27 led to nearly complete loss of pharyngeal cartilage by attenuating proliferation and blocking differentiation of pre-chondrogenic cells. Focal adhesion kinase (FAK) is a key regulator in integrin-mediated extracellular matrix (ECM) adhesion and has been proposed to function as a negative regulator of chondrogenesis. We show that FAK is downregulated in the pharyngeal arches during chondrogenesis and is a direct target of miR-27. Suppressing the accumulation of FAK in miR-27 morphants partially rescued the severe pharyngeal cartilage defects observed upon knock down of miR-27. These data support a crucial role for miR-27 in promoting chondrogenic differentiation in the pharyngeal arches through regulation of FAK.
Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
The zebrafish skeleton shares many similarities with human and other vertebrate skeletons. Over the past years, work in zebrafish has provided an extensive understanding of the basic developmental mechanisms and cellular pathways directing skeletal development and homeostasis. This review will focus on the cell biology of cartilage and bone and how the basic cellular processes within chondrocytes and osteocytes function to assemble the structural frame of a vertebrate body. We will discuss fundamental functions of skeletal cells in production and secretion of extracellular matrix and cellular activities leading to differentiation of progenitors to mature cells that make up the skeleton. We highlight important examples where findings in zebrafish provided direction for the search for genes causing human skeletal defects and also how zebrafish research has proven important for validating candidate human disease genes. The work we cover here illustrates utility of zebrafish in unraveling molecular mechanisms of cellular functions necessary to form and maintain a healthy skeleton.
© 2017 Elsevier Inc. All rights reserved.
OBJECTIVE - To investigate the role of integrin α1β1 in the progression of post-traumatic osteoarthritis (PTOA), and elucidate the contribution of epidermal growth factor receptor (EGFR) signalling to the mechanism by which integrin α1β1 might control PTOA. We hypothesised that integrin α1β1 plays a protective role in the course of PTOA and that the effect of PTOA (e.g., synovitis, loss of cartilage and growth of osteophytes) would be exacerbated in mice lacking integrin α1β1 at every time point post destabilisation of medial meniscus (DMM).
METHODS - DMM or sham surgery was performed on integrin α1-null and wild type (WT) mice and the progression of PTOA analysed at 2, 4, 8 and 12 weeks post-surgery (PS) using micro-computed tomography (microCT), histology, and immunohistochemistry. In addition, the effects of EGFR blockade were examined by treating the mice with the EGFR inhibitor erlotinib.
RESULTS - Integrin α1-null female, but not male, mice showed earlier cartilage degradation post DMM surgery compared to WT controls. Furthermore, erlotinib treatment resulted in significantly less cartilage damage in integrin α1-null but not WT mice. Independent of genotype, erlotinib treatment significantly mitigated the effects of PTOA on many tissues of female mice including meniscal and fabella bone volume, subchondral bone thickness and density and cartilage degradation. In contrast, reduced EGFR signalling had little effect on signs of PTOA in male mice.
CONCLUSION - Integrin α1β1 protects against PTOA-induced cartilage degradation in female mice partially via the reduction of EGFR signalling. Furthermore, reduction of EGFR signalling protects against the development of PTOA in female, but not male mice.
Copyright © 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Wound healing in mammals is a fibrotic process. The mechanisms driving fibrotic (as opposed to regenerative) repair are poorly understood. Herein we report that therapeutic Wnt inhibition with topical application of small-molecule Wnt inhibitors can reduce fibrosis and promote regenerative cutaneous wound repair. In the naturally stented model of ear punch injury, we found that Wnt/β-catenin pathway is activated most notably in the dermis of the wound bed early (d 2) after injury and subsides to baseline levels by d10. Topical application of either of 2 mechanistically distinct small-molecule Wnt pathway inhibitors (a tankyrase inhibitor, XAV-939, and the U.S. Food and Drug Administration-approved casein kinase activator, pyrvinium) in C57Bl/6J mice resulted in significantly increased rates of wound closure (72.3 ± 14.7% with XAV-939; and 52.1 ± 20.9% with pyrvinium) compared with contralateral controls (38.1 ± 23.0 and 40.4.± 16.7%, respectively). Histologically, Wnt inhibition reduced fibrosis as measured by α-smooth muscle actin positive myofibroblasts and collagen type I α1 synthesis. Wnt inhibition also restored skin architecture including adnexal structures in ear wounds and dermal-epidermal junction with rete pegs in excisional wounds. Additionally, in ear punch injury Wnt inhibitor treatment enabled regeneration of auricular cartilage. Our study shows that pharmacologic Wnt inhibition holds therapeutic utility for regenerative repair of cutaneous wounds.
Interleukin-6 (IL-6) and interleukin-11 (IL-11) receptors (IL-6R and IL-11R, respectively) are both expressed in osteoclasts and transduce signal via the glycoprotein130 (gp130) co-receptor, but the physiological role of this pathway is unclear. To determine the critical roles of gp130 signalling in the osteoclast, we generated mice using cathepsin K Cre (CtskCre) to disrupt gp130 signalling in osteoclasts. Bone marrow macrophages from CtskCre.gp130(f/f) mice generated more osteoclasts in vitro than cells from CtskCre.gp130(w/w) mice; these osteoclasts were also larger and had more nuclei than controls. While no increase in osteoclast numbers was observed in vivo, osteoclasts on trabecular bone surfaces of CtskCre.gp130(f/f) mice were more spread out than in control mice, but had no functional defect detectable by serum CTX1 levels or trabecular bone cartilage remnants. However, trabecular osteoblast number and mineralising surfaces were significantly lower in male CtskCre.gp130(f/f) mice compared to controls, and this was associated with a significantly lower trabecular bone volume at 12 weeks of age. Furthermore, CtskCre.gp130(f/f) mice exhibited greatly suppressed periosteal bone formation at this age, indicated by significant reductions in both double-labelled surface and mineral apposition rate. By 26 weeks of age, CtskCre.gp130(f/f) mice exhibited narrower femora, with lower periosteal and endocortical perimeters than CtskCre.gp130(w/w) controls. Since IL-6 and IL-11R global knockout mice exhibited a similar reduction in femoral width, we also assessed periosteal bone formation in those strains, and found bone forming surfaces were also reduced in male IL-6 null mice. These data suggest that IL-6/gp130 signalling in the osteoclast is not essential for normal bone resorption in vivo, but maintains both trabecular and periosteal bone formation in male mice by promoting osteoblast activity through the stimulation of osteoclast-derived "coupling factors" and "osteotransmitters", respectively.
Copyright © 2015 Elsevier Inc. All rights reserved.
PURPOSE - To quantify the characteristics of proton chemical exchange in knee cartilage in vivo by R1ρ dispersion analysis.
MATERIALS AND METHODS - Six healthy subjects (one female and five males, age range 24 to 71 y) underwent T1ρ imaging of knee cartilage on a 3T MRI scanner. Quantitative estimates of R1ρ (=1/T1ρ) were made using 5 different spin-lock durations for each of 12 different spin-lock amplitudes over the range 0 to 550Hz. When the variations of R1ρ with spin-locking strength (the R1ρ dispersion) are dominated by chemical exchange contributions, R1ρ dispersion curves can be analyzed to derive quantitative characteristics of the exchange and provide information on tissue composition. In this work, in vivo R1ρ dispersion of human knee articular cartilage at 3T was analyzed, and the exchange rates of protons between water and macromolecular hydroxyls (mainly in glycosaminoglycans) were estimated based on a theoretical model.
RESULTS - R1ρ values showed marked dispersion in articular cartilage and varied by approximately 50% between low and high values of the locking field, a change much greater than in surrounding tissues, consistent with greater contributions from chemical exchange. From the theoretical model, the exchange rates in cartilage were estimated to be in the range of 1.0-3.0kHz, and varied within the tissue. Variations within a single knee appear to be larger with increasing age.
CONCLUSION - R1ρ dispersion analysis may provide more specific information for studying cartilage biochemical composition and form the basis for quantitative evaluation of cartilage disorders.
Copyright © 2014 Elsevier Inc. All rights reserved.
Transcription of BMPs and their antagonists in precise spatiotemporal patterns is essential for proper skeletal development, maturation, maintenance, and repair. Nevertheless, transcriptional activity of these molecules in skeletal tissues beyond embryogenesis has not been well characterized. In this study, we used several transgenic reporter mouse lines to define the transcriptional activity of two potent BMP ligands, Bmp2 and Bmp4, and their antagonist, Noggin, in the postnatal skeleton. At 3 to 4 weeks of age, Bmp4 and Noggin reporter activity was readily apparent in most cells of the osteogenic or chondrogenic lineages, respectively, whereas Bmp2 reporter activity was strongest in terminally differentiated cells of both lineages. By 5 to 6 months, activity of the reporters had generally abated; however, the Noggin and Bmp2 reporters remained remarkably active in articular chondrocytes and persisted there indefinitely. We further found that endogenous Bmp2, Bmp4, and Noggin transcript levels in postnatal bone and cartilage mirrored the activity of their respective reporters in these tissues. Finally, we found that the activity of the Bmp2, Bmp4, and Noggin reporters in bone and cartilage at 3 to 4 weeks could be recapitulated in both osteogenic and chondrogenic culture models. These results reveal that Bmp2, Bmp4, and Noggin transcription persists to varying degrees in skeletal tissues postnatally, with each gene exhibiting its own cell type-specific pattern of activity. Illuminating these patterns and their dynamics will guide future studies aimed at elucidating both the causes and consequences of aberrant BMP signaling in the postnatal skeleton.
© 2014 American Society for Bone and Mineral Research.