Current state and practical recommendations on reproductive mental health: a narrative review.

Emotional disorders (EDs) are highly prevalent during the reproductive period, including pregnancy, postpartum, and women undergoing fertility treatments. International guidelines are increasingly suggesting the need to evaluate, prevent, and treat EDs in those women. The main aim of this narrative review is to summarize current practice in the field of EDs management during fertility treatments, pregnancy, and the postpartum and to propose a new technology-based model of care that helps to provide psychological care to all women who are in these periods. Four different databases (Pubmed, Scopus, Science Direct, Web of Science) were consulted. Selected keywords were related with infertility, pregnancy, postpartum, EDs, assessment, prevention, treatment, and technologies. We identified 1603 studies and 43 were included in this review. According to these studies, different face-to-face protocols already exist to manage EDs in women undergoing fertility treatments, pregnant or at the postpartum. We noticed an increased interest in developing technology-based solutions to overcome the limitations of traditional mental healthcare services. However, we also detected some issues in the use of technologies (i.e. increased attention to the postpartum or the lack of transdiagnostic approaches). Our results evidenced that there is still a need to develop modern, well-designed, and conceptually-relevant ICT-based programs to be used in women undergoing fertility treatments, pregnant or at the postpartum.

Sarcopenia in Type 2 Diabetes Mellitus: A Cross-Sectional Observational Study.

BACKGROUND: The aim of this study was to compare the prevalence of low muscle mass and sarcopenia in patients with type 2 diabetes mellitus (T2DM) versus paired controls (control group, CG) and the association between sarcopenia and chronic diabetes complications. METHODS: Men and women ≥50 years with T2DM (T2DM group, T2DMG) were recruited during routine outpatient visits. Total body densitometry and handgrip strength (HGS) were evaluated in the T2DMG and CG, while the T2DMG was also evaluated for the physical performance using the gait speed (GS) test. Sarcopenia was diagnosed according to the criteria of the Foundation for the National Institutes of Health Sarcopenia Project (FNIH). RESULTS: The study included 177 individuals in the T2DMG and 146 in the CG. The mean HGS value was lower in the T2DMG (24.4 ± 10.3 kg) compared with the CG (30.9 ± 9.15 kg), p < 0.001, with low HGS in 46 (25.9%) and 10 (9%) in the T2DMG and CG, respectively (p < 0.001). The prevalence of sarcopenia defined according to the FNIH criteria was higher in the T2DMG 23 (12.9%) compared with the CG 8 (5.4%), p < 0.03. The presence of albuminuria increased the odds of sarcopenia (odds ratio (OR) 2.84, 95% confidence interval (CI) 1.07-7.68, p=0.04) and osteoporosis (OR 3.38, 95% CI 1.12-9.89, p=0.03), even in patients with mild to moderate nephropathy. The body composition analysis showed increased odds of sarcopenia with increased percentage of total fat (%TF) in women (OR 1.18, 95% CI, 1.03-1.43, p=0.03) and men (OR 1.31, 95% CI, 1.10-1.75, p=0.01). CONCLUSION: Patients with T2DM presenting with albuminuria, osteoporosis, and increased %TF were more likely to have sarcopenia. This finding emphasizes the need for patients with T2DM to be evaluated for sarcopenia to allow for early implementation of measures to prevent or treat this disorder.

Individual differences and health in chronic pain: are sex-differences relevant?

BACKGROUND: Because psychological variables are known to intercorrelate, the goal of this investigation was to compare the unique association between several well-established psychological constructs in pain research and pain-related outcomes. Sex differences are considered because pain is experienced differently across sex groups. METHODS: Participants were 456 consecutive chronic pain patients attending a tertiary pain clinic (mean age = 58.4 years, SD = 14.8, 63.6% women). The study design was cross-sectional. Psychological constructs included personality (NEO-Five Factor Inventory), irrational thinking (General Attitudes and Beliefs Scale), and coping (Social Problem Solving Inventory). Outcomes were pain severity and interference (Brief Pain Inventory) and physical, general, and mental health status (Short Form-36). To decide whether the bivariate analyses and the two-block, multivariate linear regressions for each study outcome (block 1 = age, sex, and pain severity; block 2 = psychological variables) should be conducted with the whole sample or split by sex, we first explored whether sex moderated the relationship between psychological variables and outcomes. An alpha level of 0.001 was set to reduce the risk of type I errors due to multiple comparisons. RESULTS: The moderation analyses indicated no sex differences in the association between psychological variables and study outcomes (all interaction terms p > .05). Thus, further analyses were calculated with the whole sample. Specifically, the bivariate analyses revealed that psychological constructs were intercorrelated in the expected direction and mostly correlated with mental health and overall perceived health status. In the regressions, when controlling for age, sex, and pain severity, psychological factors as a block significantly increased the explained variance of physical functioning (ΔR2 = .037, p < .001), general health (ΔR2 = .138, p < .001), and mental health (ΔR2 = .362, p < .001). However, unique associations were only obtained for mental health and neuroticism (ß = - 0.30, p < .001) and a negative problem orientation (ß = - 0.26, p < .001). CONCLUSIONS: There is redundancy in the relationship between psychological variables and pain-related outcomes and the strength of this association is highest for mental health status. The association between psychological characteristics and health outcomes was comparable for men and women, which suggests that the same therapeutic targets could be selected in psychological interventions of pain patients irrespective of sex.

Bone mineral density and vertebral fractures and their relationship with pulmonary dysfunction in patients with chronic obstructive pulmonary disease.

To evaluate bone mineral density (BMD) and morphometric vertebral fractures (MVF) in chronic obstructive pulmonary disease (COPD) patients in comparison with two control groups. BMD was lower in the disease group (DG) and was associated with the worst disease severity and prognosis. The prevalence of MVF was high and greater in the DG than in the control groups. INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is associated with osteoporosis and vertebral fractures. It is still unclear whether the presence of fractures and changes in bone mineral density (BMD) are associated with disease severity and prognosis. The aim of this study was to evaluate BMD and morphometric vertebral fractures (MVF) in COPD patients in comparison with two control groups and to correlate these parameters with indices of COPD severity (VEF1 and GOLD) and prognosis (BODE). METHODS: This was a cross-sectional study in COPD patients (disease group, DG) who underwent BMD and vertebral fracture assessment (VFA). Two control groups were used: smokers without COPD (smoker group, SG) and healthy never-smoker individuals (never-smoker group, NSG). RESULTS: The DG comprised 121 patients (65 women, mean age 67.9 ± 8.6 years). Altered BMD was observed in 88.4% of the patients in the DG, which was more prevalent when compared with the control groups (p < 0.001). The BMD values were lower in the DG than in the control groups (p < 0.05). BMD was associated with the worst disease severity and prognosis (p < 0.05). The prevalence of MVF was high (57.8%) and greater than that in the SG (23.8%) and the NSG (14.8%; p < 0.001). The prevalence of fractures was not associated with disease severity and prognosis. CONCLUSIONS: COPD patients have a higher prevalence of MVF and low BMD, and the latter was associated with the severity and poor prognosis of the disease.

Eppur Si Muove: ferritin is essential in modulating inflammation.

Ferritin, which was only discovered in the last century, has stirred a formidable debate. Ferritin has long been appreciated as a non-specific acute-phase reactant. Several years ago, we hypothesized the contributory role of ferritin as a pathogenic molecule rather than being a product of inflammation. The latest emerging evidence provides support to this notion. Such revelation provides a step forward towards the understanding of disease conditions associated with hyperferritinaemia, and hence provide new targets for treatment modalities.

Two threshold levels of vitamin D and the prevalence of comorbidities in outpatients of a tertiary hospital.

This study evaluated the number of comorbidities between two normal values of 25OHD in outpatients during 1 year of 25OHD measurements. Five hundred twenty-nine outpatients were included, patients with 25OHD ≥ 20 and < 30 ng/mL had the higher number of comorbidities, suggesting that for this specific population, 25OHD ≥ 30 ng/mL would be more appropriate. INTRODUCTION : This study evaluated the comorbidities between two values of 25OHD in outpatients of a tertiary hospital. METHODS: This is a cross-sectional study with measures of 25OHD in 1-year period, excluding 25OHD < 20 and > 50 ng/mL, clinical research participants, and liver disease and chronic renal failure patients. Patients were divided into two groups: group 1 (G1), 25OHD ≥ 20 and < 30 ng/mL; and group 2 (G2), 250HD ≥ 30 and ≤ 50 ng/mL. Medical records were reviewed for demographic, laboratory, and comorbidity data. RESULTS: From 529 outpatients included, 319 were in G1 (53.3 ± 15.8 years, 85% women), mean 25OHD 24.8 ± 2.8 ng/mL; and 210 outpatients in G2 (56.7 ± 16.0 years, 83% women), mean 25OHD was 36.8 ± 4.8 ng/mL. G1 had the higher number of comorbidities, including altered glycemia, dyslipidemia, hypothyroidism, urinary tract diseases, arthropathy, secondary hyperparathyroidism, anemia, and neurological and psychiatric disorders. Osteoporosis and hypothyroidism were more prevalent in G2. After binary logistic regression, the variables age (OR 0.988, CI 0.97-1.00, p = 0.048), osteoporosis (OR 0.54, CI 0.36-0.80, p = 0.003), dyslipidemia (OR 1.61, CI 1.10-2.39, p = 0.015), arthropathy (OR 2.60, CI 1.40-5.10, p = 0.003), anemia (OR 15.41, CI 3.09-280.08, p = 0.008), and neurological and psychiatric diseases (OR 3.78, CI 1.98-7.88, p = 0.001) maintained significance. CONCLUSION: Patients with serum 25OHD ≥ 20 and < 30 ng/mL had higher prevalence of comorbidities compared to ≥ 30 ng/mL.

Echinostomes in Felid Coprolites from Brazil.

The first record of Echinostoma (Trematoda: Echinostomatidae) in coprolites was from a mummified human body in Minas Gerais State, Brazil. The finding raised questions on this parasite's incidence in prehistoric populations and the natural hosts of each species in remote times. Echinostomes occur worldwide and, despite the wide range of hosts, there is no record of Echinostomatidae in felines in Brazil. This study reports the finding of Echinostomatidae eggs in felid coprolites in the Furna do Estrago Archaeological Site, located in Pernambuco State in the Brazilian semiarid. Despite the possibility of false parasitism, the finding expands the distribution of this Digenea in remote times and raises the hypothesis of other cases of echinostomiasis in pre-Colombian populations.

Subtle changes in bone mineralization density distribution in most severely affected patients with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is associated with low aBMD as measured by DXA and altered microstructure as assessed by bone histomorphometry and microcomputed tomography. Knowledge of bone matrix mineralization is lacking in COPD. Using quantitative backscatter electron imaging (qBEI), we assessed cancellous (Cn.) and cortical (Ct.) bone mineralization density distribution (BMDD) in 19 postmenopausal women (62.1 ± 7.3 years of age) with COPD. Eight had sustained fragility fractures, and 13 had received treatment with inhaled glucocorticoids. The BMDD outcomes from the patients were compared with healthy reference data and were correlated with previous clinical and histomorphometric findings. In general, the BMDD outcomes for the patients were not significantly different from the reference data. Neither the subgroups of with or without fragility fractures or of who did or did not receive inhaled glucocorticoid treatment, showed differences in BMDD. However, subgroup comparison according to severity revealed 10% decreased cancellous mineralization heterogeneity (Cn.CaWidth) for the most severely affected compared with less affected patients (p=0.042) and compared with healthy premenopausal controls (p=0.021). BMDD parameters were highly correlated with histomorphometric cancellous bone volume (BV/TV) and formation indices: mean degree of mineralization (Cn.CaMean) versus BV/TV (r=0.58, p=0.009), and Cn.CaMean and Ct.CaMean versus bone formation rate (BFR/BS) (r=-0.71, p<0.001). In particular, those with lower BV/TV (<50th percentile) had significantly lower Cn.CaMean (p=0.037) and higher Cn.CaLow (p=0.020) compared with those with higher (>50th percentile) BV/TV. The normality in most of the BMDD parameters and bone formation rates as well as the significant correlations between them suggests unaffected mineralization processes in COPD. Our findings also indicate no significant negative effect of treatment with inhaled glucocorticoids on the bone mineralization pattern. However, the observed concomitant occurrence of relatively lower bone volumes with lower bone matrix mineralization will both contribute to the reduced aBMD in some patients with COPD.

Calcium metabolism, vitamin D and bone mineral density after bariatric surgery.

SUMMARY: Lower bone mineral density, vitamin D deficiency, lower lean body mass, greater loss of excess weight, and increased bone turnover are complications found after bariatric surgery correlated in the literature with increased risk of fractures. The prevention and treatment of such complications should begin immediately after surgery. INTRODUCTION: The aims of the study were to evaluate bone mass in patients undergoing bariatric surgery by the Wittgrove technique after 1 year of the procedure and correlate it with body composition, weight loss, 25OH vitamin D levels, and markers of bone metabolism. METHODS: The operated group (OG) participated in a clinical consultation; a blood sample taken and a body composition; and bone mineral density assessment by dual energy X-ray absorptiometry (DXA). The results were compared with a control group (CG). RESULTS: Fifty-six subjects in the OG and 27 in the CG were included. The bone mineral density (BMD), after the surgery, at the lumbar spine (LS) was lower in the OG than in the CG. There was a positive correlation between total body (TB) BMD with 25OHD, body mass index (BMI), and lean mass and an inverse correlation with percentage of excess weight loss (%EWL). Vitamin D deficiency was seen in 60.41% (OG) and in 16.6% (CG). PTH was higher in the OG, with secondary hyperparathyroidism in 41.7%. In 26.5% and 14.2% of the OG, ALP and OC levels were above the reference values. In <50 years, elevated values of carboxy-terminal telopeptide (CTX) were found in 66.7% of patients. A difference was observed in the variation of CTX between 12 and 18 months when compared to over 24 months. CONCLUSIONS: Lower BMD was observed, correlated with lower lean body mass and greater loss of excess weight. Vitamin D deficiency with high prevalence of secondary hyperparathyroidism and high bone turnover was detected. The prevention of bone loss should be initiated in the first months after surgery, which is a period associated with severe muscle loss and increased bone turnover.

Correlation between 25-hydroxyvitamin D levels and latitude in Brazilian postmenopausal women: from the Arzoxifene Generations Trial.

SUMMARY: We investigated vitamin D status in Brazilian cities located at different latitudes. Insufficiency (<50 nmol/L) was common (17 %), even in those living in a tropical climate. Vitamin D insufficiency increased as a function of latitude. Mean 25-hydroxyvitamin D (25(OH)D) levels in each site and latitude correlation were very high (r = -0.88; p=0.02). [corrected]. INTRODUCTION: Inadequate vitamin D, determined by low levels of 25(OH)D, has become very common despite the availability of sunlight at some latitudes. National data from a country that spans a wide range of latitudes would help to determine to what extent latitude or other factors are responsible for vitamin D deficiency. We investigated vitamin D status in cities located at different latitudes in Brazil, a large continental country. METHODS: The source is the Brazilian database from the Generations Trial (1,933 osteopenic or osteoporotic postmenopausal women (60 to 85 years old) with 25(OH)D measurements). 25(OH)D below 25 nmol/L (10 ng/mL) was an exclusion criterion. Baseline values were between fall and winter. The sites included Recife, Salvador, Rio de Janeiro, São Paulo, Curitiba, and Porto Alegre. Mean and standard deviation of 25(OH)D, age, spine and femoral neck T-score, calcium, creatinine, and alkaline phosphatase were calculated for each city. Pearson correlation was used for 25(OH)D and latitude. RESULTS: Insufficiency (<50 or <20 ng/mL) was common (329 subjects, 17 %). Vitamin D insufficiency increased as a function of latitude, reaching 24.5 % in the southernmost city, Porto Alegre. The correlation between mean 25(OH)D levels in each site and latitude was very high (r = -0.88, p < 0.0001). CONCLUSION: There is a high percentage of individuals with vitamin D insufficiency in Brazil, even in cities near the equator, and this percentage progressively increases with more southern latitudes.

Osteoporosis after solid organ transplantation.

Osteoporosis and high risk of fractures have emerged as frequent and devastating complications of organ solid transplantation process. Bone loss after organ transplant is related to adverse effects of immunosuppressive drugs on bone remodeling and bone quality. Many factors contribute to the pathogenesis of osteoporosis in transplanted patients. This review address the mechanisms of bone loss that occurs both in the early and late post-transplant periods including the contribution of the immunosuppressive agents as well as the specific features to bone loss after kidney, lung, liver and cardiac transplantation. Therapy for bone loss and prevention of fragility fracture in the transplant recipient will also be discussed.

Chronic obstructive pulmonary disease is associated with osteoporosis and low levels of vitamin D.

UNLABELLED: We did a cross-sectional analysis of chronic pulmonary obstructive disease (COPD) patients without chronic use of systemic glucocorticoids (CUG). Osteoporosis was found in 51% and bone mineral density (BMD) was correlated with severity of disease. Low levels of vitamin D were found in 94%. All COPD patients may benefit from vitamin D supplementation and screening for low BMD. INTRODUCTION: Patients with chronic pulmonary obstructive disease have low bone mineral density, caused by chronic use of systemic glucocorticoids and hypovitaminosis D. However, patients without CUG may also have low BMD. METHODS: We performed a cross-sectional analysis in 49 patients (21 men, 28 postmenopausal women), with COPD without CUG, from Brazil (25 degrees 25' S). Several markers of bone metabolism were measured, plus BMD. Osteoporosis risk factors and history of fractures were investigated. Respiratory function was assessed by venous gasometry, spirometry, and oximetry. BMD results were compared to those of 40 healthy non-smokers controls. RESULTS: COPD patients had lower BMD at all sites (p < 0.01). Osteoporosis was observed in 51%. BMD independently correlated with stage of disease (lumbar spine, R = 0.38, p = 0.01; total femur, R = 0.36, p = 0.01; femoral neck, R = 0.40, p < 0.01). Ninety-four percent had low levels of vitamin D (<30 ng/mL) and 67% had secondary hyperparathyroidism. Vitamin D was correlated with oxygen saturation (R = 0.36, p = 0.01), with lower levels in those with saturation <88% (p = 0.01). CONCLUSION: Patients with COPD without CUG have increased risk for osteoporosis. Such patients have hypovitaminosis D, which is correlated with the severity of disease. Screening for low BMD and vitamin D supplementation may be warranted to all COPD patients.

Vitamin D deficiency in patients with active systemic lupus erythematosus.

UNLABELLED: We investigated the effects of disease activity on bone metabolism in 36 patients with systemic lupus erythematosus (SLE). Changes in bone remodeling were not explained by corticosteroid use. A high prevalence of 25OHD deficiency in SLE patients indicates the need for vitamin D replacement, mainly during high disease activity periods. INTRODUCTION: We investigated the effects of SLE disease activity on bone metabolism, their relation to inflammatory cytokines and vitamin D levels. METHODS: We performed a cross-sectional analysis of 36 SLE patients classified according to the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) in high activity (group I: 12 patients, mean age 29.6 years) or in minimal activity (group II: 24 patients, mean age 30.0 years), and compared them to normal controls (group III: 26 women, 32.8 years). Serum calcium, phosphorus, parathyroid and sex hormones, bone remodeling markers, interleukin (IL)-6, soluble IL-6 receptor (sIL-6R), IL-1, tumor necrosis factor-alpha (TNF), 25-hydroxivitamin D (25OHD), and 1,25-dihydroxyvitamin D3 were measured, plus bone mineral density. RESULTS: All cytokines were significantly higher in SLE groups; IL-6 could differentiate SLE patients from controls. In group I, 25OHD levels were lower (P < 0.05), which was related to the SLEDAI (R = -0.65, P < 0.001). In multiple regression analysis, the 25OHD level was associated with SLEDAI, osteocalcin and bone-specific alkaline phosphatase. The SLEDAI score was positively correlated with all measured cytokines and especially TNF (R = 0.75, P < 0.001). CONCLUSIONS: SLE patients demonstrated changes in bone remodeling strongly related to disease activity. A high prevalence of 25OHD deficiency was observed in SLE patients, indicating the need for vitamin D replacement.

Bone turnover 18 months after a single intravenous dose of zoledronic acid.

Zoledronic acid inhibits bone resorption for up to 12 months. It is not known whether the duration of this antiresorptive effect extends beyond this period of time. The aim of this study was to evaluate the changes in bone turnover at 12 months (T12) and 18 months (T18) after a single injection of 4 mg of zoledronic acid. It is a prospective, longitudinal study, with a follow-up for 18 months. We studied male and female patients (60.5 +/- 11.0 years old), with low bone mineral density (BMD) coming from the outpatient clinic in a metabolic bone unit of a tertiary care hospital. All patients received a single intravenous dose of 4 mg of zoledronic acid, bone turnover markers [serum carboxyterminal telopeptide of type I collagen (CTX-I), bone-specific alkaline phosphatase (BSAP)] and BMD [lumbar spine (LS) and total hip (TH)] were measured at baseline, and after 12 months (T12) and 18 months (T18). Median serum CTX-I and BSAP levels were suppressed at T12 in comparison with baseline values: 0.183 to 0.039 ng/ml for CTX-I (p = 0.0002) and 16.95 to 13.96 U/l for BSAP (p = 0.005). At T18, both CTX-I and BSAP continued to be suppressed below baseline at 0.108 ng/ml and 12.23 U/l (p = 0.009 and p = 0.02, vs. T0). Significant increases in BMD at T18 as compared with T12 were observed in patients (median increase 6.1% for LS and 2.0% for TH). Zoledronic acid inhibits bone turnover effectively for 12 months, with evidence for continued suppression and gains in BMD even after 18 months.

High prevalence of vertebral deformity in premenopausal systemic lupus erythematosus patients.

In this paper we searched for vertebral deformities in a group of 70 premenopausal systemic lupus erythematosus (SLE) patients (31.8 +/- 8.1 years old) and compared them to a matched control group of 22 healthy women (32.0 +/- 8.9 years old). Patients and controls performed spine X-ray (XR) morphometry and lumbar spine and femoral neck bone mineral density (BMD). Clinical data was obtained by a questionnaire and charts review. Thoracic or lumbar spine fracture was observed in 15 (21.4%) SLE patients, while no deformities were found in the control group (P = 0.018). BMD was not different amongst SLE patients and controls and between SLE patients with or without deformities. Although BMD could not predict what patient have deformity, seven patients (46.6%) with deformity had a lumbar spine or femoral neck Z-score less than - 1 SD [median = -0.59 (-3.72 to +0.88) and -0.20 (-4.05 to + 1.87)] respectively. In addition, we found a negative correlation between number of fracture per patient and lumbar spine and femoral neck BMD (R = 0.58, P = 0.04 and R = 0.84, P = <0.0001 respectively). No significant correlation was found between number of deformities and clinical data. This is the first study to search for vertebral deformities in SLE patients and to demonstrate a high prevalence of deformities in a relative young SLE population. These findings bring up the necessity to look for spine deformities in this group of women regardless the BMD.

Regulation of the gp80 and gp130 subunits of the IL-6 receptor by sex steroids in the murine bone marrow.

Both estrogen and androgen exert their antiosteoporotic effects, at least in part, by inhibiting IL-6 production, thereby suppressing osteoclastogenesis. Several observations, however, suggest that besides increased IL-6 production, sensitivity of the osteoclastogenic process to this cytokine is altered after ovariectomy. Based on this and evidence that the ligand-binding subunit of the IL-6 receptor (gp80) is a limiting factor for the actions of IL-6 on bone, we hypothesized that sex steroids regulate expression of the IL-6 receptor as well. We report that 17beta-estradiol or dihydrotestosterone in vitro decreased the abundance of the gp80 mRNA as well as the mRNA of the signal-transducing subunit of the IL-6 receptor (gp130) in cells of the bone marrow stromal/osteoblastic lineage, and also decreased gp130 protein levels. These effects did not require new protein synthesis. In contrast to sex steroids, parathyroid hormone stimulated gp130 expression; this effect was opposed by sex steroids. Consistent with these findings, ovariectomy in mice caused an increase in expression of gp80, gp130, and IL-6 mRNAs in ex vivo bone marrow cell cultures as determined by quantitative reverse transcription (RT)-PCR, and confirmed on an individual cell basis using in situ RT-PCR. The demonstration of increased expression of the IL-6 receptor after loss of sex steroids provides an explanation for why IL-6 is important for skeletal homeostasis in the sex steroid-deficient, but not replete, state.

Activation of the Janus kinase/STAT (signal transducer and activator of transcription) signal transduction pathway by interleukin-6-type cytokines promotes osteoblast differentiation.

We have previously established that stromal/osteoblastic cells collectively express receptors for all members of the cytokine subfamily that share the gp130 signal transducer and that different receptor repertoires may be expressed at different stages of differentiation of this lineage. We have now used human (MG-63) and murine (MC3T3-E1) osteoblastic cell lines as well as primary murine calvaria cells to test the hypothesis that these receptors mediate effects of the cytokines on the biology of osteoblasts. We report that as in other cell types, all of the osteoblastic cell models responded to interleukin-6 (IL-6)-type cytokines with activation of both the JAK/STAT (Janus kinase/signal transducer and activator of transcription) and the mitogen-activated protein kinase (MAPK) pathways. In addition, IL-6-type cytokines stimulated alkaline phosphatase activity and osteocalcin expression and inhibited (MG-63), stimulated (MC3T3-E1), or had no effect (calvaria cells) on the rate of cell proliferation. The ability of a given cell type to respond to a particular member of this family of cytokines was strictly dependent on the presence of the corresponding ligand-binding subunit (alpha) of the cytokine receptor, and the magnitude of all the effects was closely correlated with the concentration of this subunit. The relative contribution of the JAK/STAT and MAPK pathways to the biological effects of the cytokines was evaluated using kinase inhibitors. Cytokine-mediated modulation of cell proliferation as well as stimulation of alkaline phosphatase activity were abrogated by tyrosine kinase inhibitors as well as a threonine/serine kinase inhibitor, but were only minimally affected by a specific inhibitor of MAPK phosphorylation. These results demonstrate that IL-6-type cytokines, besides their osteoclastogenic properties, promote differentiation of committed osteoblastic cells toward a more mature phenotype and that this action is mediated primarily via the activation of the JAK/STAT pathway.

Detection of receptors for interleukin-6, interleukin-11, leukemia inhibitory factor, oncostatin M, and ciliary neurotrophic factor in bone marrow stromal/osteoblastic cells.

The functional receptor complexes assembled in response to interleukin-6 and -11 (IL-6 and IL-11), leukemia inhibitory factor (LIF), oncostatin M (OSM), and ciliary neurotrophic factor (CNTF), all involve the signal transducer gp130: IL-6 and IL-11 induce homodimerization of gp130, while the rest heterodimerize gp130 with other gp130-related beta subunits. Some of these cytokines (IL-6, IL-11, and CNTF) also require a specificity-determining alpha subunit not directly involved in signaling. We have searched for functional receptor complexes for these cytokines in cells of the bone marrow stromal/osteoblastic lineage, using tyrosine phosphorylation of the beta subunits as a detection assay. Collectively, murine calvaria cells, bone marrow-derived murine cell lines (+/+LDA11 and MBA13.2), as well as murine (MC3T3-E1) and human (MG-63) osteoblast-like cell lines displayed all the previously recognized alpha and beta subunits of this family of receptors. However, individual cell types had different constellations of alpha and beta subunits. In addition and in difference to the other cell types examined, MC3T3-E1 cells expressed a heretofore unrecognized form of gp130; and MG-63 displayed an alternative form (type II) of the OSM receptor. These findings establish that stromal/osteoblastic cells are targets for the actions of all the members of the cytokine subfamily that shares the gp130 signal transducer; and suggest that different receptor repertoires may be expressed at different stages of differentiation of this lineage.