Spontaneous generation of functional osteoclasts from synovial fluid mononuclear cells as a model of inflammatory osteoclastogenesis

In osteoimmunology, osteoclastogenesis is understood in the context of the immune system. Today, the in vitro model for osteoclastogenesis necessitates the addition of recombinant human receptor activator of nuclear factor kappa‐B ligand (RANKL) and macrophage colony‐stimulating factor (M‐CSF). The peripheral joints of patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA) are characterized by an immune‐mediated inflammation that can lead to bone destruction. Here, we evaluate spontaneous in vitro osteoclastogenesis in cultures of synovial fluid mononuclear cells (SFMCs) activated only in vivo. SFMCs were isolated and cultured for 21 days at 0.5–1.0 × 10⁶ cells/mL in culture medium. SFMCs and healthy control peripheral blood monocytes were cultured with RANKL and M‐CSF as controls. Tartrate‐resistant acid phosphatase (TRAP) positive multinucleated cells were found in the SFMC cultures after 21 days. These cells expressed the osteoclast genes calcitonin receptor, cathepsin K, and integrin β3, formed lacunae on dentin plates and secreted matrix metalloproteinase 9 (MMP9) and TRAP. Adding RANKL and M‐CSF potentiated this secretion. In conclusion, we show that SFMCs from inflamed peripheral joints can spontaneously develop into functionally active osteoclasts ex vivo. Our study provides a simple in vitro model for studying inflammatory osteoclastogenesis.     

Trade Herbal Products and Induction of CYP2C19 and CYP2E1 in Cultured Human Hepatocytes

Abstract: The aim of this study was to evaluate in vitro the dose‐dependent induction potential of six commonly used trade herbal products on CYP2C19 and CYP2E1 metabolic activities in cultured human hepatocytes. S‐mephenytoin and chlorzoxazone were used as specific CYP substrates, respectively, and rifampicin was used as a positive induction control for both enzymes. The hepatocytes were exposed to herbal extracts in increasing and biological relevant concentrations for 72 hrs and CYP substrate metabolites were quantified by validated HPLC methodologies. The major findings were that St John's wort was the most potent CYP‐modulating herb, showing a dose‐dependent induction/inhibition of both CYP2C19 and CYP2E1, with induction at low dosages and inhibition at higher. Ginkgo biloba showed an induction/inhibition profile towards CYP2C19 which was similar but weaker than that observed for St John's wort. If cooperative mechanisms are involved is still an open question. Common sage induced CYP2C19 in a log‐linear dose‐dependent manner with increasing concentrations. Common valerian was a weak inducer of CYP2C19, while horse chestnut and cone flower were characterized as non‐inducers of CYP2C19. Only St John's wort showed an inductive effect towards CYP2E1. In addition to St John's wort, Gingko biloba and common sage should be considered as possible candidates for clinically relevant drug‐herb interactions with selected CYP2C19 substrates.     

The prevalence of peripheral arterial disease and medial arterial calcification in patients with chronic renal failure: requirements for diagnostics

BACKGROUND: Knowledge of the prevalence of peripheral arterial disease (PAD) in patients with chronic renal failure (CRF) is limited because of a lack of uniformity in disease definition and recognition. Furthermore, little is known of the prevalence of medial arterial calcification (MAC) in patients with CRF. Our goal is to study the prevalence of PAD and MAC defined by ankle brachial index (ABI) or toe brachial index (TBI) measurements in a Finnish population of patients with CRF consisting of predialysis and dialysis patients, as well as renal transplant recipients. METHODS: We examined 136 patients with CRF and 59 control subjects. Fifty-nine of the patients with CRF had moderate to severe predialysis CRF, 36 patients were on dialysis treatment, and 41 were renal transplant recipients. Mean age of patients was 51.9 +/- 11.5 years, and 39 patients (29%) had diabetes. ABI and TBI were measured by means of photoplethysmography. The definition of PAD required an ABI value of 0.90 or less, a TBI value of 0.60 or less, or a previous positive lower-extremity angiogram result. ABI values of 1.3 or greater or incompressible arteries at ankle level indicated MAC. The presence of claudication was determined by an interview. RESULTS: Prevalences of PAD on this study were 22.0% in patients with predialysis CRF, 30.6% in patients on dialysis treatment, 14.6% in renal transplant recipients, and 1.7% in the control group (P = 0.001). Prevalences of MAC were 23.7%, 41.7%, 23.1%, and 3.4% (P < 0.001), respectively. Only 9 patients had claudication, and 6 of those patients had PAD. CONCLUSION: Both asymptomatic PAD and MAC are common in patients with CRF. Therefore, we recommend the use of both ABI and TBI measurements in the evaluation of PAD in patients with CRF.