Francesco Paolo Cantatore

C-reactive protein is independently associated with total body fat, central fat, and insulin resistance in adult women

OBJECTIVE: To investigate whether C-reactive protein (CRP) concentrations are influenced by body composition, insulin resistance, and body fat distribution in healthy women.DESIGN: Cross-sectional study of CRP plasma levels in adult women.SUBJECTS: A total of 201 apparently healthy normal weight, overweight, and obese women, aged 18–60 y.MEASUREMENTS: CRP plasma levels, several fatness and body fat distribution parameters (by bioimpedance analysis and anthropometry), and insulin resistance (HOMAIR), as calculated by homeostatic model assessment.RESULTS: CRP was positively correlated with age, body mass index (BMI), waist, fasting glucose and insulin, HOMAIR, fat-free mass (FFM) and fat mass (FM). After multivariate analyses, age, HOMAIR, waist and FM maintained their independent association with CRP.CONCLUSION: Our study has shown an independent relationship of central fat accumulation and insulin resistance with CRP plasma levels, thus suggesting that mild, chronic inflammation may be a further component of the metabolic syndrome and a mediator of the atherogenic profile of this syndrome.

Osteoblast physiology in normal and pathological conditions

Osteoblasts are mononucleated cells that are derived from mesenchymal stem cells and that are responsible for the synthesis and mineralization of bone during initial bone formation and later bone remodelling. Osteoblasts also have a role in the regulation of osteoclast activity through the receptor activator of nuclear factor κ-B ligand and osteoprotegerin. Abnormalities in osteoblast differentiation and activity occur in some common human diseases such as osteoporosis and osteoarthritis. Recent studies also suggest that osteoblast functions are compromised at sites of focal bone erosion in rheumatoid arthritis.

Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group

Objectives To assess the effects of Rituximab (RTX) on skin and lung fibrosis in patients with systemic sclerosis (SSc) belonging to the European Scleroderma Trial and Research (EUSTAR) cohort and using a nested case-control design. Methods Inclusion criteria were fulfilment of American College of Rheumatology classification criteria for SSc, treatment with RTX and availability of follow-up data. RTX-treated patients were matched with control patients from the EUSTAR database not treated with RTX. Matching parameters for skin/lung fibrosis were the modified Rodnan Skin Score (mRSS), forced vital capacity (FVC), follow-up duration, scleroderma subtype, disease duration and immunosuppressive co-treatment. The primary analysis was mRSS change from baseline to follow-up in the RTX group compared with the control group. Secondary analyses included change of FVC and safety measures. Results 63 patients treated with RTX were included in the analysis. The case-control analysis in patients with severe diffuse SSc showed that mRSS changes were larger in the RTX group versus matched controls (N=25; −24.0±5.2% vs −7.7±4.3%; p=0.03). Moreover, in RTX-treated patients, the mean mRSS was significantly reduced at follow-up compared with baseline (26.6±1.4 vs 20.3±1.8; p=0.0001). In addition, in patients with interstitial lung disease, RTX prevented significantly the further decline of FVC compared with matched controls (N=9; 0.4±4.4% vs −7.7±3.6%; p=0.02). Safety measures showed a good profile consistent with previous studies in autoimmune rheumatic diseases. Conclusions The comparison of RTX treated versus untreated matched-control SSc patients from the EUSTAR cohort demonstrated improvement of skin fibrosis and prevention of worsening lung fibrosis, supporting the therapeutic concept of B cell inhibition in SSc.

Osteocalcin: Skeletal and extra‐skeletal effects

Osteocalcin (OC) is a non‐collagenous, vitamin K‐dependent protein secreted in the late stage of osteoblasts differentiation. The presence of the three residues of γ‐carbossiglutamatic acid, specific of the active form of OC protein, allows the protein to bind calcium and consequently hydroxyapatite. The osteoblastic OC protein is encoded by the bone γ‐carbossiglutamate gene whose transcription is principally regulated by the Runx2/Cbfa1 regulatory element and stimulated by vitamin D3 through a steroid‐responsive enhancer sequence. Even if data obtained in literature are controversial, the dual role of OC in bone can be presumed as follows: firstly, OC acts as a regulator of bone mineralization; secondly, OC regulates osteoblast and osteoclast activity. Recently the metabolic activity of OC, restricted to the un‐carboxylated form has been demonstrated in osteoblast‐specific knockout mice. This effect is mediated by the regulation of pancreatic β‐cell proliferation and insulin secretion and adiponectin production by adipose tissue and leads to the regulation of glucose metabolism and fat mass. Nevertheless, clinical human studies only demonstrated the correlation between OC levels and factors related to energy metabolism. Thus further investigations in humans are required to demonstrate the role of OC in the regulation of human energy metabolism. Moreover, it is presumable that OC also acts on blood vessels by inducing angiogenesis and pathological mineralization. This review highlights the recent studies concerning skeletal and extra‐skeletal effects of OC. J. Cell. Physiol. 228: 1149–1153, 2013.

Vitamin D and the Immune System

Evidence of the role of vitamin D in the regulation of T and B cells, macrophages, dendritic cells, and keratinocytes continues to accumulate and provides a link between vitamin D and many autoimmune diseases, including Crohn’s disease, juvenile diabetes mellitus, multiple sclerosis, asthma, and rheumatoid arthritis. Considering the influence of vitamin D on the immune system, it may have potential as a treatment for immune-mediated diseases, even if additional research is required to better quantify dosage. But the biggest obstacle to its clinical use is its potent hypercalcemic effect. The calcium status of the host may influence the effect of vitamin D on immunity.

Efficacy of a soy rich diet in preventing postmenopausal osteoporosis: the Menfis randomized trial

OBJECTIVES To compare the effect of a soy rich diet and hormone replacement therapy (HRT) on the main biomarkers of bone turnover and bone mineral density (BMD) at postmenopausal age. METHODS 187 healthy asymptomatic postmenopausal women, aged 39-60, were recruited and randomized into a soy rich diet group, a HRT group, and a control group. Bone biomarkers and BMD were evaluated at baseline and after 6 months at the end of the study. RESULTS Diet is not as effective as HRT in reducing the postmenopausal turnover; however diet stimulates bone osteoblastic activity, as evidenced by significant increase in osteocalcin concentrations. BMD decreases significantly only in the control group, but not in the intervention groups. CONCLUSIONS Our data suggest that soy products could be effective in reducing the risk of osteoporosis in asymptomatic postmenopausal women, but our findings should be confirmed before recommending the diet as a valid alternative to HRT.

Lymphocytes and synovial fluid fibroblasts support osteoclastogenesis through RANKL, TNFα, and IL‐7 in an in vitro model derived from human psoriatic arthritis

Psoriatic arthritis (PsA) is an inflammatory joint disease, characterized by extensive bone resorption, whose mechanisms have not been fully elucidated. Thus, in the present study we investigated the involvement of RANKL, TNFα, and IL‐7 in the osteoclastogenesis of PsA patients. In vitro osteoclastogenesis models, consisting of unfractionated and T‐cell‐depleted mononuclear cells from peripheral blood (PBMCs) and synovial fluid (SFMCs) of 20 PsA patients as well as from healthy donors were studied. Freshly isolated T and B cells from PBMCs and T cells and fibroblasts from SFMCs of PsA patients were subjected to RT‐PCR to detect the levels of RANKL, TNFα, and IL‐7. Osteoclastogenesis was studied in the presence of RANK‐Fc, anti‐TNFα, and anti IL‐7 functional antibodies. We demonstrate that lymphocytes and fibroblasts support osteoclast (OC) formation in PsA patients through the production of osteoclastogenic cytokines. In particular, OC formation was completely abolished in unstimulated T cell‐depleted PBMC cultures, and reduced by approximately 70% in unstimulated T cell‐depleted SFMC cultures. Freshly isolated T cells from PBMCs and SFMCs of PsA patients overexpressed RANKL and TNFα, while fibroblasts from synovial fluid produced only RANKL. We show that the presence of RANK‐Fc and/or anti‐TNFα functional antibodies reduced OC formation. Moreover, T and B cells from PBMCs as well as T cells and fibroblasts from SFMCs expressed IL‐7 mRNA. Finally, the anti‐IL‐7 functional antibody significantly reduced osteoclastogenesis. Our results suggest that fibroblasts, B and T lymphocytes support OC formation by producing RANKL, TNFα, and IL‐7, contributing to the aggressive bone resorption in PsA patients. Copyright

Effect of oestrogen replacement on bone metabolism and cytokines in surgical menopause

SummaryThe effect of oestrogen replacement on bone metabolism and serum cytokine levels (IL1, IL6) was investigated in surgical menopause. The study included 40 female subjects; 10 healthy premenopausal women underwent total hysterectomy without oophorectomy. Thirty healthy premenopausal women underwent total hysterectomy with bilateral oophorectomy. They were randomly divided into 3 groups of 10 subjects. The first group received natural estradiol (0,05 mg/day) for 6 months; the second group received natural estradiol (0,05 mg/day) and medroxyprogesteron acetate (10 mg/day) for 6 months, the third group received no therapy.Calcium-phosphorus metabolism, inflammatory indices, serum IL1 and IL6 levels were tested before and 6 months after surgery in all patients.A significant increase in serum alkaline phosphatase, urinary cross-links, serum PTH and IL1-IL6 was observed in the untreated women with total hysterectomy and oophorectomy.No significant variation in any of the parameters considered was observed in patients treated with oestrogen, in those treated with oestrogens and medroxyprogesteron nor in patients without oophorectomy. These results in human “in vivo” confirm that ovarian steroids play an important role in regulating the production of IL1 and IL6 which could regulate bone resorption.

Response of human osteoblasts to polymethylmetacrylate In vitro.

Abstract. The effects of a polymethylmetacrylate (PMMA) powder with a diameter between 0.5 and 25 μm have been studied in vitro on several human osteoblast populations obtained from different sources. Parameters of cell activity such as cell growth, collagen synthesis, osteocalcin, and interleukin-6 (IL-6) production have been evaluated. Cell proliferation and collagen synthesis were inhibited after exposure to bone cement, whereas osteocalcin and IL-6 production were stimulated. These results suggest that PMMA particles could affect osteoblast activity in a way that could contribute, together with other factors, to periprosthetic osteolysis through two different pathways: a reduced periprosthetic bone formation due to the reduced osteoblast proliferation and collagen synthesis, and an osteoblast-mediated activation of osteoclastic bone resorption as suggested by the increased osteocalcin and IL-6 synthesis. In fact, osteocalcin has been demonstrated to have a role in osteoclast recruitment to bone surfaces, and IL-6 is known to induce osteoclastogenesis and to directly stimulate bone resorption.

Mast cells in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic disease of joints that is characterized by inflammation, abnormal cellular and humoral immune responses, and synovial hyperplasia. Mast cells (MCs) are involved in several of these inflammatory and immune events. MC-derived mediators induce edema, destroy connective tissue, and are involved in lymphocyte chemotaxis and infiltration and in pathological fibrosis of RA joints. Moreover, MCs are involved in angiogenesis during RA, and their proteolytic activity results in cartilage destruction and bone remodeling. Lastly, MCs could be a target in the treatment of RA.