Bone quality relies on hyaluronan synthesis - Insights from mice with complete knockout of hyaluronan synthase expression.

Bone consists of a complex mineralised matrix that is maintained by a controlled equilibrium of synthesis and resorption by different cell types. Hyaluronan (HA) is an important glycosaminoglycan in many tissues including bone. Previously, the importance of HA synthesis for bone development during embryogenesis has been shown.

Targeting CDC42 reduces skeletal degeneration after hematopoietic stem cell transplantation.

Osteopenia and osteoporosis are common long-term complications of the cytotoxic conditioning regimen for hematopoietic stem cell transplantation (HSCT). We examined mesenchymal stem and progenitor cells (MSPCs), which include skeletal progenitors, from mice undergoing HSCT. Such MSPCs showed reduced fibroblastic colony-forming units frequency, increased DNA damage, and enhanced occurrence of cellular senescence, whereas there was a reduced bone volume in animals that underwent HSCT.

Journey through discovery of 75 years glucocorticoids: evolution of our knowledge of glucocorticoid receptor mechanisms in rheumatic diseases.

For three-quarters of a century, glucocorticoids (GCs) have been used to treat rheumatic and autoimmune diseases. Over these 75 years, our understanding of GCs binding to nuclear receptors, mainly the glucocorticoid receptor (GR) and their molecular mechanisms has changed dramatically. Initially, in the late 1950s, GCs were considered important regulators of energy metabolism.

SNX10 regulates osteoclastogenic cell fusion and osteoclast size in mice.

Bone-resorbing osteoclasts (OCLs) are formed by differentiation and fusion of monocyte precursor cells, generating large multinucleated cells. Tightly regulated cell fusion during osteoclastogenesis leads to formation of resorption-competent OCLs, whose sizes fall within a predictable physiological range. The molecular mechanisms that regulate the onset of OCL fusion and its subsequent arrest are, however, largely unknown.

Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids.

Glucocorticoids represent the mainstay of therapy for a broad spectrum of immune-mediated inflammatory diseases. However, the molecular mechanisms underlying their anti-inflammatory mode of action have remained incompletely understood. Here we show that the anti-inflammatory properties of glucocorticoids involve reprogramming of the mitochondrial metabolism of macrophages, resulting in increased and sustained production of the anti-inflammatory metabolite itaconate and consequent inhibition of the inflammatory response.

Acetylation-induced proteasomal degradation of the activated glucocorticoid receptor limits hormonal signaling.

Glucocorticoid (GC) signaling is essential for mounting a stress response, however, chronic stress or prolonged GC therapy downregulates the GC receptor (GR), leading to GC resistance. Regulatory mechanisms that refine this equilibrium are not well understood. Here, we identify seven lysine acetylation sites in the amino terminal domain of GR, with lysine 154 (Lys) in the AF-1 region being the dominant acetyl-acceptor.

Depletion of slow-cycling PDGFRαADAM12 mesenchymal cells promotes antitumor immunity by restricting macrophage efferocytosis.

The capacity to survive and thrive in conditions of limited resources and high inflammation is a major driver of tumor malignancy. Here we identified slow-cycling ADAM12PDGFRα mesenchymal stromal cells (MSCs) induced at the tumor margins in mouse models of melanoma, pancreatic cancer and prostate cancer. Using inducible lineage tracing and transcriptomics, we demonstrated that metabolically altered ADAM12 MSCs induced pathological angiogenesis and immunosuppression by promoting macrophage efferocytosis and polarization through overexpression of genes such as Gas6, Lgals3 and Csf1.

Osseointegration of photodynamic active biomaterials for bone regeneration in an animal bone model over a period of 12 months.

Objectives: Previous efforts led to the development of two different polymeric biomaterials for periodontal regeneration with antibacterial photodynamic surface activity. The present study aimed to investigate osseointegration and bone formation of both materials in an ovine model.

Methods: Both biomaterials: 1) urethane dimethacrylate-based Biomaterial 1 (BioM1) and 2) tri-armed oligoester-urethane methacrylate-based Biomaterial 2 (BioM2) are enriched with beta-tri-calcium phosphate and the photosensitizer meso-tetra(hydroxyphenyl)chlorin (mTHPC).

Unique Gene Expression Signature in Periadrenal Adipose Tissue Identifies a High Blood Pressure Group in Patients With Cushing Syndrome.

Background: Cushing syndrome (CS) is a rare disease caused by excess cortisol levels with high cardiovascular morbidity and mortality. Hypertension in CS promotes hypercortisolism-associated cardiovascular events. Adipose tissue is a highly plastic tissue with most cell types strongly affected by the excess cortisol exposure.

Signalling by senescent melanocytes hyperactivates hair growth.

Niche signals maintain stem cells in a prolonged quiescence or transiently activate them for proper regeneration. Altering balanced niche signalling can lead to regenerative disorders. Melanocytic skin nevi in human often display excessive hair growth, suggesting hair stem cell hyperactivity.

Why Animal Experiments Are Still Indispensable in Bone Research: A Statement by the European Calcified Tissue Society.

Major achievements in bone research have always relied on animal models and in vitro systems derived from patient and animal material. However, the use of animals in research has drawn intense ethical debate and the complete abolition of animal experimentation is demanded by fractions of the population. This phenomenon is enhanced by the reproducibility crisis in science and the advance of in vitro and in silico techniques.

Intact GR dimerization is critical for restraining plasma ACTH levels during chronic psychosocial stress.

Male C57BL/6N mice exposed to the chronic subordinate colony housing (CSC; 19 days) paradigm, a preclinically validated model of chronic psychosocial stress, are characterized by unaffected basal morning plasma corticosterone (CORT) concentrations despite adrenal and pituitary hyperplasia and increased adrenocorticotropic hormone (ACTH) plasma concentrations, compared with single-housed control (SHC) mice. However, as CSC mice are still able to show an increased CORT secretion towards novel heterotypic stressors, these effects might reflect an adaptation rather than a functional breakdown of general hypothalamus-pituitary-adrenal (HPA) axis functionality. In the present study we used male mice of a genetically modified mouse line, to investigate whether genetically-driven ACTH overexpression compromises adaptational processes occurring at the level of the adrenals during CSC exposure.

The calcium channel Orai1 is required for osteoblast development: Studies in a chimeric mouse with variable in vivo Runx-cre deletion of Orai-1.

The calcium-selective ion channel Orai1 has a complex role in bone homeostasis, with defects in both bone production and resorption detected in Orai1 germline knock-out mice. To determine whether Orai1 has a direct, cell-intrinsic role in osteoblast differentiation and function, we bred Orai1 flox/flox (Orai1fl/fl) mice with Runx2-cre mice to eliminate its expression in osteoprogenitor cells. Interestingly, Orai1 was expressed in a mosaic pattern in Orai1fl/fl-Runx2-cre bone.

Energy saver: Monocytes hibernate in bone marrow upon fasting.

Immune functions are influenced by the nutritional state. In a recent publication in Immunity, Janssen et al. unveil that a fasting-induced glucocorticoid release makes monocytes move from blood into the bone marrow.

Deletion of the chondrocyte glucocorticoid receptor attenuates cartilage degradation through suppression of early synovial activation in murine posttraumatic osteoarthritis.

Objective: Disruption of endogenous glucocorticoid signalling in bone cells attenuates osteoarthritis (OA) in aged mice, however, the role of endogenous glucocorticoids in chondrocytes is unknown. Here, we investigated whether deletion of the glucocorticoid receptor, specifically in chondrocytes, also alters OA progression.

Design: Knee OA was induced by surgical destabilisation of the medial meniscus (DMM) in male 22-week-old tamoxifen-inducible glucocorticoid receptor knockout (chGRKO) mice and their wild-type (WT) littermates (n = 7-9/group).

Glucocorticoid activation of anti-inflammatory macrophages protects against insulin resistance.

Insulin resistance (IR) during obesity is linked to adipose tissue macrophage (ATM)-driven inflammation of adipose tissue. Whether anti-inflammatory glucocorticoids (GCs) at physiological levels modulate IR is unclear. Here, we report that deletion of the GC receptor (GR) in myeloid cells, including macrophages in mice, aggravates obesity-related IR by enhancing adipose tissue inflammation due to decreased anti-inflammatory ATM leading to exaggerated adipose tissue lipolysis and severe hepatic steatosis.

Immunoglobulin G-dependent inhibition of inflammatory bone remodeling requires pattern recognition receptor Dectin-1.

Immunoglobulin G (IgG) antibodies are major drivers of inflammation during infectious and autoimmune diseases. In pooled serum IgG (IVIg), however, antibodies have a potent immunomodulatory and anti-inflammatory activity, but how this is mediated is unclear. We studied IgG-dependent initiation of resolution of inflammation in cytokine- and autoantibody-driven models of rheumatoid arthritis and found IVIg sialylation inhibited joint inflammation, whereas inhibition of osteoclastogenesis was sialic acid independent.

Downregulation of the Autism Spectrum Disorder Gene Decreases Bone Mass in Male Mice.

Mutations of the postsynaptic scaffold protein Shank2 lead to autism spectrum disorders (ASD). These patients frequently suffer from higher fracture risk. Here, we investigated whether Shank2 directly regulates bone mass.

Macrophagic AMPKα1 orchestrates regenerative inflammation induced by glucocorticoids.

Macrophages are key cells after tissue damage since they mediate both acute inflammatory phase and regenerative inflammation by shifting from pro-inflammatory to restorative cells. Glucocorticoids (GCs) are the most potent anti-inflammatory hormone in clinical use, still their actions on macrophages are not fully understood. We show that the metabolic sensor AMP-activated protein kinase (AMPK) is required for GCs to induce restorative macrophages.

Glucocorticoid receptor and RAS: an unexpected couple in cancer.

Constitutively activated rat sarcoma (RAS) GTPases are one of the major drivers of tumor growth and are difficult drug targets. The glucocorticoid receptor (GR), a nuclear receptor primarily acting in the nucleus, is a potent modulator of inflammation and regulator of metabolism and cell growth. Emerging evidence has revealed that GR modulates RAS-dependent signaling and RAS activation.

Increased osteoclastogenesis contributes to bone loss in the Costello syndrome mouse model.

RAS GTPases are ubiquitous GDP/GTP-binding proteins that function as molecular switches in cellular signalling and control numerous signalling pathways and biological processes. Pathogenic mutations in genes severely affect cellular homeostasis, leading to cancer when occurring in somatic cells and developmental disorders when the germline is affected. These disorders are generally termed as RASopathies and among them Costello syndrome (CS) is a distinctive entity that is caused by specific germline mutations.

Validation of Mct8/Oatp1c1 dKO mice as a model organism for the Allan-Herndon-Dudley Syndrome.

Objective: The Allan-Herndon-Dudley syndrome (AHDS) is a severe disease caused by dysfunctional central thyroid hormone transport due to functional loss of the monocarboxylate transporter 8 (MCT8). In this study, we assessed whether mice with concomitant deletion of the thyroid hormone transporters Mct8 and the organic anion transporting polypeptide (Oatp1c1) represent a valid preclinical model organism for the AHDS.

Methods: We generated and metabolically characterized a new CRISPR/Cas9 generated Mct8/Oatp1c1 double-knockout (dKO) mouse line for the clinical features observed in patients with AHDS.

Could a phase model help to improve translational animal research?

Background: Animal models are widely applied in medical research for different purposes. In particular, results from translational experiments may be used for subsequent clinical development. However, transferability of these findings to the human organism is controversial.