Osteoclast activity sculpts craniofacial form to permit sensorineural patterning in the zebrafish skull.

Efforts to understand the morphogenesis of complex craniofacial structures have largely focused on the role of chondrocytes and osteoblasts. Along with these bone-creating cells, bone-resorbing osteoclasts are critical in homeostasis of adult skeletal structures, but there is currently limited information on their role in the complex morphogenetic events of craniofacial development. Fundamental aspects of skull formation and general skeletal development are conserved from zebrafish to mammals.

celsr1a is essential for tissue homeostasis and onset of aging phenotypes in the zebrafish.

The use of genetics has been invaluable in defining the complex mechanisms of aging and longevity. Zebrafish, while a prominent model for vertebrate development, have not been used systematically to address questions of how and why we age. In a mutagenesis screen focusing on late developmental phenotypes, we identified a new mutant that displays aging phenotypes at young adult stages.

Unique and non-redundant function of paralogues in regulation and evolution of post-embryonic development of the zebrafish.

Evolution is replete with reuse of genes in different contexts, leading to multifunctional roles of signaling factors during development. Here, we explore osteoclast regulation during skeletal development through analysis of colony-stimulating factor 1 receptor () function in the zebrafish. A primary role of Csf1r signaling is to regulate the proliferation, differentiation and function of myelomonocytic cells, including osteoclasts.

A role for G protein-coupled receptor 137b in bone remodeling in mouse and zebrafish.

G protein-coupled receptor 137b (GPR137b) is an orphan seven-pass transmembrane receptor of unknown function. In mouse, Gpr137b is highly expressed in osteoclasts in vivo and is upregulated during in vitro differentiation. To elucidate the role that GPR137b plays in osteoclasts, we tested the effect of GPR137b deficiency on osteoclast maturation and resorbing activity.

The skeletal phenotype of achondrogenesis type 1A is caused exclusively by cartilage defects.

Inactivating mutations in the ubiquitously expressed membrane trafficking component GMAP-210 (encoded by ) cause achondrogenesis type 1A (ACG1A). ACG1A is surprisingly tissue specific, mainly affecting cartilage development. Bone development is also abnormal, but as chondrogenesis and osteogenesis are closely coupled, this could be a secondary consequence of the cartilage defect.

Methotrexate and low-dose prednisolone downregulate osteoclast function by decreasing receptor activator of nuclear factor-κβ expression in monocytes from patients with early rheumatoid arthritis.

Objective: Rheumatoid arthritis (RA) is a systemic, immune-mediated inflammatory disease that ultimately leads to bone erosions and joint destruction. Methotrexate (MTX) slows bone damage but the mechanism by which it acts is still unknown. In this study, we aimed to assess the effect of MTX and low-dose prednisolone (PDN) on circulating osteoclast (OC) precursors and OC differentiation in patients with RA.

Clcn7 as a new mouse model of Albers-Schönberg disease.

Dominant negative mutations in CLCN7, which encodes a homodimeric chloride channel needed for matrix acidification by osteoclasts, cause Albers-Schönberg disease (also known as autosomal dominant osteopetrosis type 2). More than 25 different CLCN7 mutations have been identified in patients affected with Albers-Schönberg disease, but only one mutation (Clcn7) has been introduced in mice to create an animal model of this disease. Here we describe a mouse with a different osteopetrosis-causing mutation (Clcn7).

Improving the DNA specificity and applicability of base editing through protein engineering and protein delivery.

We recently developed base editing, a genome-editing approach that enables the programmable conversion of one base pair into another without double-stranded DNA cleavage, excess stochastic insertions and deletions, or dependence on homology-directed repair. The application of base editing is limited by off-target activity and reliance on intracellular DNA delivery. Here we describe two advances that address these limitations.

Corrigendum: Ankylosing Spondylitis Patients Have Impaired Osteoclast Gene Expression in Circulating Osteoclast Precursors.

[This corrects the article on p. 5 in vol. 4, PMID: 28191455.

Effect of Tumor Necrosis Factor Inhibitor Therapy on Osteoclasts Precursors in Rheumatoid Arthritis.

. Tumor necrosis factor (TNF) increases circulating osteoclast (OC) precursors numbers by promoting their proliferation and differentiation. The aim of this study was to assess the effect of TNF inhibitors (TNFi) on the differentiation and activity of OC in rheumatoid arthritis (RA) patients.

Ankylosing Spondylitis Patients Have Impaired Osteoclast Gene Expression in Circulating Osteoclast Precursors.

Introduction: Ankylosing spondylitis (AS) is typically characterized by focal bone overgrowth and also by systemic bone loss. We hypothesize that the increased osteoproliferation found in AS might be partially due to reduced ability of osteoclast precursors (OCPs) to differentiate into osteoclasts (OCs). Therefore, our aim was to characterize bone remodeling and pro-osteoclastogenesis inflammatory environment, monocytes' phenotype, and osteoclast differentiation in AS patients.

Effect of Tumor Necrosis Factor Inhibitor Therapy on Osteoclasts Precursors in Ankylosing Spondylitis.

Introduction: Ankylosing Spondylitis (AS) is characterized by excessive local bone formation and concomitant systemic bone loss. Tumor necrosis factor (TNF) plays a central role in the inflammation of axial skeleton and enthesis of AS patients. Despite reduction of inflammation and systemic bone loss, AS patients treated with TNF inhibitors (TNFi) have ongoing local bone formation.

At the moment of occurrence of a fragility hip fracture, men have higher mechanical properties values in comparison with women.

Background: It is well established that males have lower fracture risk in comparison with females, which suggests a higher bone resistance in men. The aim of our study was to find out if in older patients with hip fragility fractures, gender has also an impact on trabecular bone material behaviour, specifically to determine whether trabecular mechanical properties under compressive loading differ between men and women who suffered a fragility hip fracture.

Methods: Femoral epiphyses were consecutively collected during hip replacement surgery due to proximal femur fragility fracture.

Bone histomorphometry revisited.

Bone histomorphometry is defined as a quantitative evaluation of bone micro architecture, remodelling and metabolism. Bone metabolic assessment is based on a dynamic process, which provides data on bone matrix formation rate by incorporating a tetracycline compound. In the static evaluation, samples are stained and a semi-automatic technique is applied in order to obtain bone microarchitectural parameters such as trabecular area, perimeter and width.

Protective effect of an ERAP1 haplotype in ankylosing spondylitis: investigating non-MHC genes in HLA-B27-positive individuals.

Objective: The association of non-MHC genes with AS has been recently suggested. We aimed to investigate the association of the ERAP1, IL23R and TNFSF15 regions and the susceptibility to and protection from AS in HLA-B27-positive individuals.

Methods: A total of 200 unrelated AS patients and 559 healthy unrelated subjects, all HLA-B27 positive, were tested.

Rheumatoid arthritis bone fragility is associated with upregulation of IL17 and DKK1 gene expression.

Our aim was to compare bone gene expression in rheumatoid arthritis (RA) and primary osteoporosis (OP) patients. Secondary aims were to determine the association of gene expression of the Wnt/β-catenin signaling pathway with inflammatory cytokines in the bone microenvironment and to assess the serum levels of Wnt/β-catenin proteins in both groups. RA patients referred for hip replacement surgery were recruited.

Low osteocalcin/collagen type I bone gene expression ratio is associated with hip fragility fractures.

Introduction: Osteocalcin (OC) is the most abundant non-collagenous bone protein and is determinant for bone mineralization. We aimed to compare OC bone expression and serum factors related to its carboxylation in hip fragility fracture and osteoarthritis patients. We also aimed to identify which of these factors were associated with worse mechanical behavior and with the hip fracture event.

Smoking is a predictor of worse trabecular mechanical performance in hip fragility fracture patients.

Clinical risk factors (CRFs) are established predictors of fracture events. However, the influence of individual CRFs on trabecular mechanical fragility is still a subject of debate. In this study, we aimed to assess differences, adjusted for CRFs, between bone macrostructural parameters measured in ex-vivo specimens from hip fragility fracture patients and osteoarthritis patients, and to determine whether individual CRFs could predict trabecular bone mechanical behavior in hip fragility fractures.

Lymphotoxin-α 252 A>G polymorphism: a link between disease susceptibility and dyslipidemia in rheumatoid arthritis?

Objective: Rheumatoid arthritis (RA) is associated with higher levels of inflammatory mediators and with a more atherogenic lipid profile. Dyslipidemia can be present years before arthritis develops. Lymphotoxin-α (LTA) is a cytokine that mediates proinflammatory responses while also participating in lipid homeostasis, and its transcriptional activity is in part genetically determined.

Upregulation of inflammatory genes and downregulation of sclerostin gene expression are key elements in the early phase of fragility fracture healing.

Background: Fracture healing is orchestrated by a specific set of events that culminates in the repair of bone and reachievement of its biomechanical properties. The aim of our work was to study the sequence of gene expression events involved in inflammation and bone remodeling occurring in the early phases of callus formation in osteoporotic patients.

Methodology/principal Findings: Fifty-six patients submitted to hip replacement surgery after a low-energy hip fracture were enrolled in this study.

Alterations on peripheral blood B-cell subpopulations in very early arthritis patients.

Objective: To characterize circulating B-cell subpopulations of arthritis patients with <6 weeks of disease duration.

Methods: Peripheral blood samples were collected from very early untreated polyarthritis patients, with <6 weeks of disease duration, for flow cytometric evaluation of B-cell subpopulations. Samples from patients who were later diagnosed as RA [very early RA (VERA)] were also collected 4-6 weeks after starting a low dose of prednisone (5-10 mg) and 4 months after reaching the minimum effective dose of MTX.

Chronic arthritis leads to disturbances in the bone collagen network.

Introduction: In this study we used a mice model of chronic arthritis to evaluate if bone fragility induced by chronic inflammation is associated with an imbalance in bone turnover and also a disorganization of the bone type I collagen network.

Methods: Serum, vertebrae and femur bones were collected from eight-month-old polyarthritis SKG mice and controls. Strength of the femoral bones was evaluated using three-point bending tests and density was assessed with a pycnometer.