Transcriptional profiles discriminate bone marrow-derived and synovium-derived mesenchymal stem cells

Previous studies have reported that mesenchymal stem cells (MSC) may be isolated from the synovial membrane by the same protocol as that used for synovial fibroblast cultivation, suggesting that MSC correspond to a subset of the adherent cell population, as MSC from the stromal compartment of the bone marrow (BM). The aims of the present study were, first, to better characterize the MSC derived from the synovial membrane and, second, to compare systematically, in parallel, the MSC-containing cell populations isolated from BM and those derived from the synovium, using quantitative assays. Fluorescent-activated cell sorting analysis revealed that both populations were negative for CD14, CD34 and CD45 expression and that both displayed equal levels of CD44, CD73, CD90 and CD105, a phenotype currently known to be characteristic of BM-MSC. Comparable with BM-MSC, such MSC-like cells isolated from the synovial membrane were shown for the first time to suppress the T-cell response in a mixed lymphocyte reaction, and to express the enzyme indoleamine 2,3-dioxygenase activity to the same extent as BM-MSC, which is a possible mediator of this suppressive activity. Using quantitative RT-PCR these data show that MSC-like cells from the synovium and BM may be induced to chondrogenic differentiation and, to a lesser extent, to osteogenic differentiation, but the osteogenic capacities of the synovium-derived MSC were significantly reduced based on the expression of the markers tested (collagen type II and aggrecan or alkaline phosphatase and osteocalcin, respectively). Transcription profiles, determined with the Atlas Human Cytokine/Receptor Array, revealed discrimination between the MSC-like cells from the synovial membrane and the BM-MSC by 46 of 268 genes. In particular, activin A was shown to be one major upregulated factor, highly secreted by BM-MSC. Whether this reflects a different cellular phenotype, a different amount of MSC in the synovium-derived population compared with BM-MSC adherent cell populations or the impact of a different microenvironment remains to be determined. In conclusion, although the BM-derived and synovium-derived MSC shared similar phenotypic and functional properties, both their differentiation capacities and transcriptional profiles permit one to discriminate the cell populations according to their tissue origin

Endocrine Disrupting Chemicals Interfere With Leydig Cell Hormone Pathways During Testicular Descent in Idiopathic Cryptorchidism

Cryptorchidism, a frequent genital malformation in male newborn, remains in most cases idiopathic. On the basis of experimental, epidemiological, and clinical data, it has been included in the testicular dysgenesis syndrome and believed to be influenced, together with genetic and anatomic factors, by maternal exposure to endocrine disrupting chemicals (EDCs). Here, we analyze how EDCs may interfere with the control of testicular descent, which is regulated by two Leydig cell hormones, testosterone, and insulin like peptide 3 (INSL3)

Isolated follicle-stimulating hormone (FSH) deficiency in two infertile men without FSH β gene mutation: Case report and literature review

International audienceOBJECTIVE:Congenital FSH deficiency is an exceptional cause of male infertility most often attributed to FSH β gene mutations. The few published cases report azoospermia, severe testicular hypotrophy and normal testosterone levels associated with normal virilization. We report the exploration of two young men aged 26 and 27 years with severe sperm abnormalities, moderate testicular hypotrophy and isolated FSH deficiency.METHODS:Several FSH, LH, total testosterone and inhibin B assays and FSH β gene sequencing were performed.RESULTS:FSH was almost undetectable at baseline and poorly responsive to GnRH test, whereas LH was normal at baseline and increased after GnRH test. Testosterone levels were within the adult range, while inhibin B levels were upper-normal to high. No FSH β gene mutations were found. Exogenous FSH treatment was followed by spontaneous pregnancy in one case and required intra-cytoplasmic sperm injection (ICSI) in the other.CONCLUSIONS:The paradoxical high levels of inhibin B reflect the presence of function

Mitotane (op’DDD) restores growth and puberty in nine children with Cushing’s disease

International audienceTo investigate whether low-dose mitotane (up to 2 g/day) could be a temporary therapeutic alternative to transsphenoidal surgery (TSS) in pediatric Cushing’s disease (CD). Twenty-eight patients with CD aged 12.2 years (± 2.2) were referred to our center. We compared nine patients treated with mitotane alone for at least 6 months to 13 patients cured after surgery. Primary outcomes were changes in growth velocity, BMI and pubertal development. The following results were obtained: (1) Mitotane improved growth velocity z-scores (−3.8 (±0.3) vs −0.2 (±0.6)), BMI z-scores (2.1 (±0.5) vs 1.2 (±0.5) s.d.) and pubertal development. After 1 year on mitotane, the mean BMI z-score was not significantly different in both groups of patients. (2) Control of cortisol secretion was delayed and inconsistent with mitotane used as monotherapy. (3) Side effects were similar to those previously reported, reversible and dose dependent: unspecific digestive symptoms, concentration or memory problems, physical exhaustion, adrenal insufficiency and hepatitis. (4) In one patient, progressive growth of a pituitary adenoma was observed over 40 months of mitotane treatment, allowing selective adenomectomy by TSS. In conclusions, low-dose mitotane can restore growth velocity and pubertal development and decrease BMI in children with CD, even without optimal control of cortisol secretion. It may promote pituitary tumor growth thus facilitating second-line TSS. However, given its possibly life-threatening side effects (transient adrenal insufficiency and hepatitis), and in the absence of any reliable follow-up procedures, this therapy may be difficult to manage and should always be initiated and monitored by specialized teams.</p

191 PLASMA LEVELS OF D-TRP-6-LH-RH (DECAPEPTYL) AFTER INTRAMUSCULAR INJECTION OF LONG-ACTING MICROCAPSULES IN CHILDREN TREATED FOR PRECOCIOUS PUBERTY (PP)

The efficacy of periodic administration of Decapeptyl microcapsules upon symptoms of PP has been previously reported (Roger et al., ESPE meeting 1984, abstract 22). A sensitive radioimmuno assay of the analogue was developped using an antiserum raised in rabbit which exhibited unsignificant cross reactivity with native LH-RH or LH-RH fragments (Mason-Garcia et al.,Proc.Natl. Acad. Sci., USA, in press). Iodinated D-Trp-6-LH-RH was used as a tracer. Fifty μl antiserum diluted at 1/2500 , 50 μl tracer, 100 μl standard (or unknown plasma), 100 μl plasma pool (or phosphate buffer 0.01 M, pH 7.5) were incubated for 24 h. Free and bound were separated by PEG. NSB of the plasma pool and of 40 different child samples were respectively 6.2± 0.4 and 6.3± 0.4% (mean±SD). Bo was 20%. Intraassay CV were 12 and 7% for mean plasma levels of 100 and 370 pg/ml respectively. The detec tion limit was 57 pg/ml. Five children received intramuscularly (IM) on days 1, 21 and every 28 days thereafter, 1.5 mg Decapeptyl microcapsules. Plasma levels were on days 3, 7, 14, and 21 (pg/ml, mean±SEM) 312±57, 242±65, 145±78 and 171±87. Decapeptyl was undetectable in most of samples on day 28 after injection. This study demonstrates that significant Decapeptyl levels are maintained for at least 21 days after a single IM injection

Reversal of a Blunted Follicle-Stimulating Hormone by Chemotherapy in an Inhibin B–Secreting Adrenocortical Carcinoma

International audienceAdrenocortical carcinomas (ACCs) are revealed in 60% of cases by steroid hypersecretion. Alternatively, it is uncommon to observe a paraneoplastic syndrome due to a peptide oversecretion

Loss of Anti-Müllerian Hormone Signaling in Mice Affects Trabecular Bone Mass in a Sex- and Age-Dependent Manner

Ovariectomy-induced osteoporosis in mice results from an abrupt loss of ovarian sex steroids. Anti-Müllerian hormone knockout (AMHKO) mice show a gradual but accelerated ovarian aging, and therefore may better resemble osteoporosis following natural menopause. To study the impact of AMH signaling deficiency on bone, we compared trabecular and cortical bone parameters in 2-, 4-, 10-, and 16-month-old male and female wild-type (WT), AMHKO, and AMH type II receptor knockout (MRKI) mice using micro computed tomography (microCT). Goldner's staining was performed to confirm the observed bone phenotype. Both male and female AMHKO and MRKI mice showed age-dependent loss of trabecular bone (P < 0.001). However, reproductive-aged female AMHKO and MRKI mice had higher BV/TV compared with WT (P < 0.001), coinciding with increased growing follicle numbers (P < 0.05) and increased estrus inhibin B levels (AMHKO: P < 0.001; MRKI: P < 0.05) but normal inhibin A, estrogen, and progesterone levels. In aged female AMHKO and MRKI mice BV/TV did not differ from WT mice due to greater trabecular bone loss between 10 and 16 months compared with WT mice. At these ages, AMHKO and MRKI mice had reduced growing follicle numbers (P < 0.05) and reduced inhibin B levels (P < 0.001). At age 10 months, female MRKI mice had increased cortical bone parameters compared with WT mice (P < 0.01). Bone parameters of male AMHKO and MRKI mice did not differ from male WT mice. In conclusion, AMH signaling deficiency results in a sex- and age-dependent effect on predominantly trabecular bone. Our results further suggest that reproductive hormones beyond estrogen may contribute to bone homeostasis

Endocrine disrupting chemicals interfere With leydig cell hormone pathways during testicular descent in idiopathic Cryptorchidism

International audienceCryptorchidism, a frequent genital malformation in male newborn, remains in most cases idiopathic. On the basis of experimental, epidemiological, and clinical data, it has been included in the testicular dysgenesis syndrome and believed to be influenced, together with genetic and anatomic factors, by maternal exposure to endocrine disrupting chemicals (EDCs). Here, we analyze how EDCs may interfere with the control of testicular descent, which is regulated by two Leydig cell hormones, testosterone, and insulin like peptide 3 (INSL3)