Giant cell arteritis: update on pathogenesis and clinical implications.

Purpose Of Review: Giant cell arteritis (GCA) is an age-related autoimmune disease with a complex pathogenesis that involves several pathogenic mechanisms. This review provides recent critical insights into novel aspects of GCA pathogenesis.

Recent Findings: The use of novel approaches, including multiomic techniques, has uncovered notable findings that broaden the understanding of GCA pathogenesis.

Disentangling the detrimental effects of local from systemic adipose tissue dysfunction on articular cartilage in the knee.

Objective: Obesity increases osteoarthritis (OA) risk due to adipose tissue dysfunction with associated metabolic syndrome and excess weight. Lipodystrophy syndromes exhibit systemic metabolic and inflammatory abnormalities similar to obesity without biomechanical overloading. Here, we used lipodystrophy mouse models to investigate the effects of systemic versus intra-articular adipose tissue dysfunction on the knee.

Vascular disease persistence in giant cell arteritis: are stromal cells neglected?

Giant cell arteritis (GCA), the most common systemic vasculitis, is characterised by aberrant interactions between infiltrating and resident cells of the vessel wall. Ageing and breach of tolerance are prerequisites for GCA development, resulting in dendritic and T-cell dysfunction. Inflammatory cytokines polarise T-cells, activate resident macrophages and synergistically enhance vascular inflammation, providing a loop of autoreactivity.

Osteoarthritis year in review 2023: Biology.

Great progress continues to be made in our understanding of the multiple facets of osteoarthritis (OA) biology. Here, we review the major advances in this field and progress towards therapy development over the past year, highlighting a selection of relevant published literature from a PubMed search covering the year from the end of April 2022 to the end of April 2023. The selected articles have been arranged in themes.

BMP signaling: A significant player and therapeutic target for osteoarthritis.

Objective: To explore the significance of BMP signaling in osteoarthritis (OA) etiology, and thereafter propose a disease-modifying therapy for OA.

Methods: To examine the role of the BMP signaling in pathogenesis of OA, an Anterior Cruciate Ligament Transection (ACLT) surgery was performed to incite OA in C57BL/6J mouse line at postnatal day 120 (P120). Thereafter, to investigate whether activation of BMP signaling is necessary and sufficient to induce OA, we have used conditional gain- and loss-of-function mouse lines in which BMP signaling can be activated or depleted, respectively, upon intraperitoneal injection of tamoxifen.

Towards disease modification in osteoarthritis.

In December 2022, Gerwin et al published in Nature Medicine that the C-terminal portion of angiopoietin-like 3, called LNA043, has chondroprotective and cartilage-regenerative properties. Molecular data from an experimental medicine phase I study suggested potential efficacy in humans. Here, we respond to and complement a commentary from Vincent and Conaghan and discuss unresolved issues and the potential of this molecule as a disease-modifying osteoarthritis drug.

Spatial Lipidomic Profiling of Mouse Joint Tissue Demonstrates the Essential Role of PHOSPHO1 in Growth Plate Homeostasis.

Lipids play a crucial role in signaling and metabolism, regulating the development and maintenance of the skeleton. Membrane lipids have been hypothesized to act as intermediates upstream of orphan phosphatase 1 (PHOSPHO1), a major contributor to phosphate generation required for bone mineralization. Here, we spatially resolve the lipid atlas of the healthy mouse knee and demonstrate the effects of PHOSPHO1 ablation on the growth plate lipidome.

Taxonomy of fibroblasts and progenitors in the synovial joint at single-cell resolution.

Objectives: Fibroblasts in synovium include fibroblast-like synoviocytes (FLS) in the lining and + connective-tissue fibroblasts in the sublining. We aimed to investigate their developmental origin and relationship with adult progenitors.

Methods: To discriminate between -lineage cells deriving from the embryonic joint interzone and other -expressing fibroblasts and progenitors, adult mice were used and cartilage injury was induced to activate progenitors.

A cholinergic neuroskeletal interface promotes bone formation during postnatal growth and exercise.

The autonomic nervous system is a master regulator of homeostatic processes and stress responses. Sympathetic noradrenergic nerve fibers decrease bone mass, but the role of cholinergic signaling in bone has remained largely unknown. Here, we describe that early postnatally, a subset of sympathetic nerve fibers undergoes an interleukin-6 (IL-6)-induced cholinergic switch upon contacting the bone.

Targeting the IL-6-Yap-Snail signalling axis in synovial fibroblasts ameliorates inflammatory arthritis.

Objective: We aimed to understand the role of the transcriptional co-factor Yes-associated protein (Yap) in the molecular pathway underpinning the pathogenic transformation of synovial fibroblasts (SF) in rheumatoid arthritis (RA) to become invasive and cause joint destruction.

Methods: Synovium from patients with RA and mice with antigen-induced arthritis (AIA) was analysed by immunostaining and qRT-PCR. SF were targeted using and mice, crossed with fluorescent reporters for cell tracing and mice for conditional ablation.

Human Mesenchymal Stromal Cells Enhance Cartilage Healing in a Murine Joint Surface Injury Model.

Human umbilical cord (hUC)- or bone marrow (hBM)-derived mesenchymal stromal cells (MSCs) were evaluated as an allogeneic source of cells for cartilage repair. We aimed to determine if they could enhance healing of chondral defects with or without the recruitment of endogenous cells. hMSCs were applied into a focal joint surface injury in knees of adult mice expressing tdTomato fluorescent protein in cells descending from Gdf5-expressing embryonic joint interzone cells.

Evaluation of adjunctive mycophenolate for large vessel giant cell arteritis.

Objectives: GCA patients with large vessel involvement (LV-GCA) experience greater CS requirements and higher relapse rates compared with classical cranial GCA. Despite the distinct disease course, interventions in LV-GCA have yet to be investigated specifically. This study aimed to evaluate the CS-sparing effect and tolerability of first-line mycophenolate in LV-GCA.

Identification of the skeletal progenitor cells forming osteophytes in osteoarthritis.

Objectives: Osteophytes are highly prevalent in osteoarthritis (OA) and are associated with pain and functional disability. These pathological outgrowths of cartilage and bone typically form at the junction of articular cartilage, periosteum and synovium. The aim of this study was to identify the cells forming osteophytes in OA.

Stratified glucocorticoid monotherapy is safe and effective for most cases of giant cell arteritis.

Objectives: High-dose glucocorticoids anchor standard care in GCA but are associated with significant toxicity. We aimed to evaluate the safety and effectiveness of a stratified approach to glucocorticoid tapering. The strategy aggressively reduced glucocorticoid doses in those manifesting an adequate early response to treatment, with a view to minimizing glucocorticoid complications.

Agrin induces long-term osteochondral regeneration by supporting repair morphogenesis.

Cartilage loss leads to osteoarthritis, the most common cause of disability for which there is no cure. Cartilage regeneration, therefore, is a priority in medicine. We report that agrin is a potent chondrogenic factor and that a single intraarticular administration of agrin induced long-lasting regeneration of critical-size osteochondral defects in mice, with restoration of tissue architecture and bone-cartilage interface.

Regulation of Gdf5 expression in joint remodelling, repair and osteoarthritis.

Growth and Differentiation Factor 5 (GDF5) is a key risk locus for osteoarthritis (OA). However, little is known regarding regulation of Gdf5 expression following joint tissue damage. Here, we employed Gdf5-LacZ reporter mouse lines to assess the spatiotemporal activity of Gdf5 regulatory sequences in experimental OA following destabilisation of the medial meniscus (DMM) and after acute cartilage injury and repair.

The burden of metabolic syndrome on osteoarthritic joints.

Background: The prevalence of osteoarthritis (OA) increases with obesity, with up to two thirds of the elderly obese population affected by OA of the knee. The metabolic syndrome (MetS), frequently associated with central obesity and characterised by elevated waist circumference, raised fasting plasma glucose concentration, raised triglycerides, reduced high-density lipoproteins, and/or hypertension, is implicated in the pathogenesis of OA. This narrative review discusses the mechanisms involved in the influence of MetS on OA, with a focus on the effects on macrophages and chondrocytes.

Immunostaining of Skeletal Tissues.

Immunohistochemistry (IHC) is a routinely used technique in clinical diagnosis of pathological conditions and in basic and translational research. It combines anatomical, immunological, and biochemical methods and relies on the specific binding of an antibody to an antigen. Using the technique with mineralized tissues is more challenging than with soft tissues.

Targeting anti-chondrogenic factors for the stimulation of chondrogenesis: A new paradigm in cartilage repair.

Trauma and age-related cartilage disorders represent a major global cause of morbidity, resulting in chronic pain and disability in patients. A lack of effective therapies, together with a rapidly aging population, creates an impressive clinical and economic burden on healthcare systems. In this scenario, experimental therapies based on transplantation or in situ stimulation of skeletal Mesenchymal Stem/progenitor Cells (MSCs) have raised great interest for cartilage repair.

Stem cell-based therapeutic strategies for cartilage defects and osteoarthritis.

The gold standard cell therapy for repair of articular cartilage defects is autologous chondrocyte implantation, with good outcomes long-term. Mesenchymal stromal/stem cells (MSCs) from bone marrow or connective tissues such as fat are being pursued as alternatives for cartilage repair, and are trialled via intra-articular administration in patients with knee osteoarthritis. Early-phase clinical studies concur on safety and provide some promising insight into efficacy, but the mechanism of action remains unclear.

Adipose specific disruption of seipin causes early-onset generalised lipodystrophy and altered fuel utilisation without severe metabolic disease.

Objective: Mutations to the BSCL2 gene disrupt the protein seipin and cause the most severe form of congenital generalised lipodystrophy (CGL). Affected individuals exhibit a near complete loss of white adipose tissue (WAT) and suffer from metabolic disease. Seipin is critical for adipocyte development in culture and mice with germline disruption to Bscl2 recapitulate the effects of BSCL2 disruption in humans.

The potential role of adult stem cells in the management of the rheumatic diseases.

Adult stem cells are considered as appealing therapeutic candidates for inflammatory and degenerative musculoskeletal diseases. A large body of preclinical research has contributed to describing their immune-modulating properties and regenerative potential. Additionally, increasing evidence suggests that stem cell differentiation and function are disrupted in the pathogenesis of rheumatic diseases.

Joint morphogenetic cells in the adult mammalian synovium.

The stem cells that safeguard synovial joints in adulthood are undefined. Studies on mesenchymal stromal/stem cells (MSCs) have mainly focused on bone marrow. Here we show that lineage tracing of Gdf5-expressing joint interzone cells identifies in adult mouse synovium an MSC population largely negative for the skeletal stem cell markers Nestin-GFP, Leptin receptor and Gremlin1.

Mesenchymal stem cells for the management of rheumatoid arthritis: immune modulation, repair or both?

Purpose Of Review: Mesenchymal stromal/stem cells (MSCs) have potent anti-inflammatory and immunomodulatory properties, in addition to their ability to form cartilage and bone. The purpose of this review is to highlight recent developments and current knowledge gaps in our understanding of the protective effects of MSCs against inflammatory arthritis, and to discuss their clinical exploitation for the treatment of rheumatoid arthritis (RA).

Recent Findings: The weight of evidence for protective mechanisms of exogenously administered MSCs is on immunomodulatory effects, including inhibition of dendritic cell maturation, polarization of macrophages to an anti-inflammatory phenotype, and activation of regulatory T cells, thereby dampening inflammation and preventing joint damage.