Activin A Receptor Type 1 Research Articles

DIPG-51. ACVR1 MUTATIONS PROMOTE TUMOR GROWTH IN MODELS OF DIFFUSE INTRINSIC PONTINE GLIOMA

Mutations in the gene encoding activin A receptor type 1 (ACVR1) are found in approximately 25% of diffuse intrinsic pontine gliomas (DIPGs), a pediatric glioma with 2-year survival rate of less than 10%. ACVR1mutations frequently coincide with activating PIK3CA or PIK3R1 mutations, indicating a potential cooperative effect of BMP and PI3K signaling in gliomagenesis. We used genetically engineered mice with inducible knock-in of Acvr1R206H or Pik3caE545K alleles, such that cre-mediated recombination resulted in expression of the gain of function mutated genes from their endogenous promoters at physiological levels. Cre-mediated deletion in GFAP-CreER;Pik3caE545K/+;p53cKO mice (Pik3ca;p53) mediated Trp53 deletion and expression of Pik3caE545K in glial progenitors, and spontaneously induced high-grade glioma (HGG) in mice with complete penetrance. Heterozygous knock-in of the Acvr1R206H allele accelerated tumorigenesis and impaired survival in Pik3ca;p53 mice (Acvr1;Pik3ca;p53). Transcriptomic analysis of Acvr1;Pik3ca;p53 tumors compared to Pik3ca;p53 littermate controls, as in patient-derived tumors, revealed broad molecular signatures associated with cell fate commitment and chromosome maintenance. Pharmacologic inhibition of ACVR1 was sufficient to impair growth in human patient-derived DIPG cell lines. Together, our studies show that ACVR1 activation promotes tumor growth in spontaneous mouse HGG and patient-derived DIPG cells, suggesting that ACVR1 inhibition may produce a clinically significant therapeutic effect in DIPG.

Involvement of activin a receptor type 1 (ACVR1) in the pathogenesis of primary focal hyperhidrosis

The pathogenesis of primary focal hyperhidrosis (PFH) is still not clear. PFH is thought to be a genetic disease. Whether activin A receptor type 1 (ACVR1) is involved in the pathogenesis of PFH is unknown. In this study, the expression of ACVR1 in sweat glands of patients with PAH was detected by western blot and immunofluorescence. The primary sweat gland cells obtained from primary axillary hyperhidrosis (PAH) patients were transfected with acvr1 vector. Cell proliferation, apoptosis and cell cycling of gland cells were measured after transfection with acvr1 vector. The mRNA and protein expression of aquaporin 5 (AQP5) and Na:K:2Cl Cotransporter 1 (NKCC1/SLC12A2) were detected. Our data showed that ACVR1 expression in axillary sweat gland tissue of PAH patients was significantly higher than that of normal control group. The function of ACVR1 was further investigated in the gland cells obtained from PAH patients. Compared with NC group, ACVR1 overexpression significantly promoted the proliferation of sweat gland cells and inhibited the apoptosis of sweat gland cells. Meanwhile, ACVR1 overexpression significantly reduced the percentage of cells in G0/G1 and G2/M phases, and increased the percentage of cells in S phase. In addition, ACVR1 overexpression significantly promoted the expression of AQP5 and NKCC1 at both mRNA and protein levels. Together, ACVR1 expression is related to PFH and ACVR1 overexpression can promote the proliferation of sweat gland cells and inhibit apoptosis by promoting the expression of AQP5 and NKCC1.

BMP10 preserves cardiac function through its dual activation of SMAD-mediated and STAT3-mediated pathways

Bone morphogenetic protein 10 (BMP10) is a cardiac peptide growth factor belonging to the transforming growth factor β superfamily that critically controls cardiovascular development, growth, and maturation. It has been shown that BMP10 elicits its intracellular signaling through a receptor complex of activin receptor-like kinase 1 with morphogenetic protein receptor type II or activin receptor type 2A. Previously, we generated and characterized a transgenic mouse line expressing BMP10 from the α-myosin heavy chain gene promoter and found that these mice have normal cardiac hypertrophic responses to both physiological and pathological stimuli. In this study, we report that these transgenic mice exhibit significantly reduced levels of cardiomyocyte apoptosis and cardiac fibrosis in response to a prolonged administration of the β-adrenoreceptor agonist isoproterenol. We further confirmed this cardioprotective function with a newly generated conditional Bmp10 transgenic mouse line, in which Bmp10 was activated in adult hearts by tamoxifen. Moreover, the intraperitoneal administration of recombinant human BMP10 was found to effectively protect hearts from injury, suggesting potential therapeutic utility of using BMP10 to prevent heart failure. Gene profiling and biochemical analyses indicated that BMP10 activates the SMAD-mediated canonical pathway and, unexpectedly, also the signal transducer and activator of transcription 3 (STAT3)-mediated signaling pathway both in vivo and in vitro Additional findings further supported the notion that BMP10's cardioprotective function likely is due to its dual activation of SMAD- and STAT3-regulated signaling pathways, promoting cardiomyocyte survival and suppressing cardiac fibrosis.

Activin A receptor type 1–mediated BMP signaling regulates RANKL-induced osteoclastogenesis via canonical SMAD-signaling pathway

Bone morphogenetic proteins (BMPs) are important mediators of osteoclast differentiation. Although accumulating evidence has implicated BMPs in osteoblastogenesis, the mechanisms by which BMPs regulate osteoclastogenesis remain unclear. Activin A receptor type 1 (ACVR1) is a BMP type 1 receptor essential for skeletal development. Here, we observed that BMP-7, which preferentially binds to ACVR1, promotes osteoclast differentiation, suggesting ACVR1 is involved in osteoclastogenesis. To investigate this further, we isolated osteoclasts from either Acvr1-floxed mice or mice with constitutively-activated Acvr1 (caAcvr1) carrying tamoxifen-inducible Cre driven by a ubiquitin promotor and induced Cre activity in culture. Osteoclasts from the Acvr1-floxed mice had reduced osteoclast numbers and demineralization activity, whereas those from the caAcvr1-mutant mice formed large osteoclasts and demineralized pits, suggesting that BMP signaling through ACVR1 regulates osteoclast fusion and activity. It is reported that BMP-2 binds to BMPR1A, another BMP type 1 receptor, whereas BMP-7 binds to ACVR1 to activate SMAD1/5/9 signaling. Here, Bmpr1a-disrupted osteoclasts displayed reduced phospho-SMAD1/5/9 (pSMAD1/5/9) levels when induced by BMP-2, whereas no impacts on pSMAD1/5/9 were observed when induced by BMP-7. In contract, Acvr1-disrupted osteoclasts displayed reduced pSMAD1/5/9 levels when induced either by BMP-2 or BMP-7, suggesting that ACVR1 is the major receptor for transducing BMP-7 signals in osteoclasts. Indeed, LDN-193189 and LDN-212854, which specifically block SMAD1/5/9 phosphorylation, inhibited osteoclastogenesis of caAcvr1-mutant cells. Moreover, increased BMP signaling promoted nuclear translocation of nuclear factor-activated T-cells 1 (NFATc1), which was inhibited by LDN treatments. Taken together, ACVR1-mediated BMP-SMAD signaling activates NFATc1, a regulatory protein crucial for receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis.

Skeletal malformations and developmental arthropathy in individuals who have fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is primarily a disease of progressive heterotopic ossification (HO) leading to impaired mobility throughout life. An additional diagnostic feature is a characteristic malformation of the great toes. The culpable gene for FOP,ACVR1 (activin A receptor type 1) has a clear effect on the induction of extra-skeletal bone formation. However, this bone morphogenetic protein (BMP) pathway receptor is expressed widely throughout skeletal development and has a seminal role in axial and appendicular chondrogenesis, prompting suspicion of widespread bone and joint defects in those with ACVR1 mutations. We analyzed baseline whole body (minus skull) computed tomographic (CT) scans of 113 individuals with classic clinical features of FOP and the ACVR1 (R206H) mutation who were enrolled in a non-interventional natural history study ((NCT02322255)) for skeletal malformations, atypical morphology, intra-articular synovial osteochondromatosis, developmental arthropathy, and associated degenerative joint phenotypes. Individuals were evaluated in three age groups: 4-13; 14-25; and 25-56 years old, based on historical models of FOP disease progression. We found widespread evidence of developmental arthropathy throughout the axial and appendicular skeleton in all age groups (61M, 52F; ages: 4-56 years). Asymmetric narrowing and subchondral sclerosis were present throughout the joints of the normotopic skeleton and osteophytes were common in the hips and knees of individuals who have FOP in all age groups. The costovertebral joints, intervertebral facet joints, and proximal tibio-fibular joints frequently showed partial or total intra-articular ankylosis, particularly after age 13. The hips of FOP subjects are frequently malformed and dysplastic. We also found evidence of degenerative joint phenotypes after age 13, particularly in the spine, sacro-iliac joints, and lower limbs. The effects of ACVR1 mutation on the normotopic skeletons of individuals who have FOP extend beyond malformation of the great toes and include both morphological defects and developmental arthropathy. Associated degenerative joint disease occurring at multiple sites starts in adolescence and progresses throughout life. These phenotypes appear to be uncoupled from heterotopic bone formation, indicating a potential role for ACVR1 in the development and progression of degenerative joint disease. FOP is a disease of not only progressive heterotopic ossification, but also widespread and extensive developmental arthropathy and associated degenerative joint disease. These findings have relevance for understanding the natural history of FOP and for designing and evaluating clinical trials with emerging therapeutics.

Fibrodysplasia ossificans progressiva: lessons learned from a rare disease.

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare and severely disabling autosomal dominant disease that is yet to be clearly understood. The purpose of this review is to present recent literature on pathophysiology, clinical features, diagnosis and treatment of FOP. FOP is characterized by congenital great toe deformity and progressive heterotopic ossifications in connective tissue. Heterotopic ossifications occur after painful flare-ups that can arise spontaneously or can be triggered by minor trauma. Each flare-up ultimately causes restriction of related-joint, and along with the others eventually leads to immobility. Death is usually caused by pulmonary complications because of chest wall involvement. The causative gene of FOP is activin A receptor type 1 (ACVR1), a bone morphogenetic protein-signalling component, which normally acts to inhibit osteoblastogenesis. The treatment of FOP is still preventive and supportive. Although there are still gaps in the underlying mechanism of FOP, effective treatment options, such as potential pharmacologic targets and cell-based therapies are promising for the future. Some of these were tested without a clinical trial setting, and are currently in the process of evidence-based research.

The ACVR1 gene is significantly associated with growth traits in Chinese beef cattle

Activin A receptor type 1 (ACVR1) annotated for its involvement in some key signaling pathways is one promising candidate for economic traits. The aim of this study was to analyze its phenotypic effects on cattle growth traits. Four variations including two intronic Indels and two exonic SNPs were detected in 840 cattle from five Chinese cattle breeds by DNA-pool sequencing. Variations g.33008_33024del (rs385690012) and g.41793C>T (rs458497709) were significantly associated with cattle growth traits which were cannon bone circumference (CBC), chest girth (CG), chest depth (CD) (P < 0.05) using reduced animal general linear model. Additionally, the two significant loci of the studied populations were in Hardy-Weinberg equilibrium and had relatively high heterozygosity which was close to 2p*(1 − p). Conclusively, the two variations g.33008_33024del and g.41793C>T can be used as molecular marker for marker-assisted selection in beef cattle breeding.

Distinctive role of ACVR1 in dentin formation: requirement for dentin thickness in molars and prevention of osteodentin formation in incisors of mice.

Dentin is a major component of teeth that protects dental pulp and maintains tooth health. Bone morphogenetic protein (BMP) signaling is required for the formation of dentin. Mice lacking a BMP type I receptor, activin A receptor type 1 (ACVR1), in the neural crest display a deformed mandible. Acvr1 is known to be expressed in the dental mesenchyme. However, little is known about how BMP signaling mediated by ACVR1 regulates dentinogenesis. To explore the role of ACVR1 in dentin formation in molars and incisors in mice, Acvr1 was conditionally disrupted in Osterix-expressing cells (designated as cKO). We found that loss of Acvr1 in the dental mesenchyme led to dentin dysplasia in molars and osteodentin formation in incisors. Specifically, the cKO mice exhibited remarkable tooth phenotypes characterized by thinner dentin and thicker predentin, as well as compromised differentiation of odontoblasts in molars. We also found osteodentin formation in the coronal part of the cKO mandibular incisors, which was associated with a reduction in the expression of odontogenic gene Dsp and an increase in the expression of osteogenic gene Bsp, leading to an alteration of cell fate from odontoblasts to osteoblasts. In addition, the expressions of WNT antagonists, Dkk1 and Sost, were downregulated and B-catenin was up-regulated in the cKO incisors, while the expression levels were not changed in the cKO molars, compared with the corresponding controls. Our results indicate the distinct and critical roles of ACVR1 between incisors and molars, which is associated with alterations in the WNT signaling related molecules. This study demonstrates for the first time the physiological roles of ACVR1 during dentinogenesis.

MicroRNA-384 inhibits the progression of breast cancer by targeting ACVR1.

Breast cancer is the leading cause of cancer-related deaths in females worldwide. Triple-negative breast cancer (TNBC) accounts for 15% of all breast cancer cases and has a poorer prognosis than other subtypes. Moreover, the treatment for breast cancer, especially for TNBC, remains unsatisfactory. Therefore, novel therapies are urgently needed. Microribonucleic acids (miRNAs) are a class of biomarkers and therapeutic targets in many types of cancers. In the present study, the expression of miR-384 was explored in GSE58606 and in fresh breast cancer tissues by qPCR. The results showed that miR-384 was decreased in breast cancer, especially in TNBC. The results of MTT, colony formation, soft agar, Transwell migration, wound healing and the tumorigenesis assay demonstranted that overexpression of miR-384 inhibited the proliferation and migration of breast cancer in vitro and in vivo; knockdown of miR-384 enhanced the proliferation and migration of breast cancer. In addition, luciferase assay showed that Activin A receptor type 1 (ACVR1) was a direct target of miR-384 and is involved in the inhibitory effects of miR-384 on breast cancer progression. Furthermore, this study indicated that ACVR1 activated the Wnt/β-catenin signaling pathway in breast cancer. In conclusion, our findings revealed functional and mechanistic links between miR-384 and ACVR1 in the progression of breast cancer. miR-384 not only plays an important role in the progression of breast cancer, but has promise as a potential therapeutic target for breast cancer especially for TNBC.

Pharmacokinetics and Disposition of Momelotinib Revealed a Disproportionate Human Metabolite—Resolution for Clinical Development

Momelotinib (MMB), a small-molecule inhibitor of Janus kinase (JAK)1/2 and of activin A receptor type 1 (ACVR1), is in clinical development for the treatment of myeloproliferative neoplasms. The pharmacokinetics and disposition of [14C]MMB were characterized in a single-dose, human mass-balance study. Metabolism and the pharmacologic activity of key metabolites were elucidated in multiple in vitro and in vivo experiments. MMB was rapidly absorbed following oral dosing with approximately 97% of the radioactivity recovered, primarily in feces with urine as a secondary route. Mean blood-to-plasma [14C] area under the plasma concentration-time curve ratio was 0.72, suggesting low association of MMB and metabolites with blood cells. [14C]MMB-derived radioactivity was detectable in blood for ≤48 hours, suggesting no irreversible binding of MMB or its metabolites. The major circulating human metabolite, M21 (a morpholino lactam), is a potent inhibitor of JAK1/2 and ACVR1 in vitro. Estimation of pharmacological activity index suggests M21 contributes significantly to the pharmacological activity of MMB for the inhibition of both JAK1/2 and ACVR1. M21 was observed in disproportionately higher amounts in human plasma than in rat or dog, the rodent and nonrodent species used for the general nonclinical safety assessment of this molecule. This discrepancy was resolved with additional nonclinical studies wherein the circulating metabolites and drug-drug interactions were further characterized. The human metabolism of MMB was mediated primarily by multiple cytochrome P450 enzymes, whereas M21 formation involved initial P450 oxidation of the morpholine ring followed by metabolism via aldehyde oxidase.

A BRIEF OVERVIEW OF THE VERY RARE FIBRODYSPLASIA OSSIFICANS PROGRESSIVA (STONE MAN SYNDROME)

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare disorder with only about 800 million people affected worldwide. It occurs as a result of the mutation in Activin A receptor type 1 (ACVR1) gene leading to extraskeletal structure formation which further gradually progresses to skeletal deformities and premature death. This disorder is also known as stone man syndrome as it causes joints to become frozen resulting in mobility impairment. It is generally identified in early childhood and affects almost every organ. Though there is no approved treatment for this rare disorder, researchers are in progress. Supportive therapy and care can help the patients to some extent by providing temporary relief. In this review, we will briefly outline the information regarding FOP which is difficult to diagnose and whose misdiagnosis is dangerous.

Activin receptor type 2A (ACVR2A) functions directly in osteoblasts as a negative regulator of bone mass

Bone and skeletal muscle mass are highly correlated in mammals, suggesting the existence of common anabolic signaling networks that coordinate the development of these two anatomically adjacent tissues. The activin signaling pathway is an attractive candidate to fulfill such a role. Here, we generated mice with conditional deletion of activin receptor (ACVR) type 2A, ACVR2B, or both, in osteoblasts, to determine the contribution of activin receptor signaling in regulating bone mass. Immunohistochemistry localized ACVR2A and ACVR2B to osteoblasts and osteocytes. Primary osteoblasts expressed activin signaling components, including ACVR2A, ACVR2B, and ACVR1B (ALK4) and demonstrated increased levels of phosphorylated Smad2/3 upon exposure to activin ligands. Osteoblasts lacking ACVR2B did not show significant changes in vitro However, osteoblasts deficient in ACVR2A exhibited enhanced differentiation indicated by alkaline phosphatase activity, mineral deposition, and transcriptional expression of osterix, osteocalcin, and dentin matrix acidic phosphoprotein 1. To investigate activin signaling in osteoblasts in vivo, we analyzed the skeletal phenotypes of mice lacking these receptors in osteoblasts and osteocytes (osteocalcin-Cre). Similar to the lack of effect in vitro, ACVR2B-deficient mice demonstrated no significant change in any bone parameter. By contrast, mice lacking ACVR2A had significantly increased femoral trabecular bone volume at 6 weeks of age. Moreover, mutant mice lacking both ACVR2A and ACVR2B demonstrated sustained increases in trabecular bone volume, similar to those in ACVR2A single mutants, at 6 and 12 weeks of age. Taken together, these results indicate that activin receptor signaling, predominantly through ACVR2A, directly and negatively regulates bone mass in osteoblasts.

Preclinical Modeling of ACVR1-Dependent Hepcidin Production and Anemia By Momelotinib

▪Patients with myelofibrosis (MF) often develop anemia and frequently become dependent on red blood cell transfusions. Elevated levels of hepcidin in MF patients suggest that deregulated iron homeostasis is a driver of anemia in MF (Pardanani et al., Am J Hematol, 2013). A phase 2 study in MF patients demonstrated that momelotinib (MMB) treatment resulted in improvement of anemia (Pardanani et al., Blood, 2013, ASH Suppl). We have demonstrated that in addition to inhibiting JAK1/2, MMB also inhibits the bone morphogenetic protein receptor kinase, activin A receptor type 1 (ACVR1), a key regulator of hepcidin production in hepatocytes (Asshoff et al., Blood, 2015, ASH Suppl). This work supports a model by which the improvement of anemia observed in MF patients with MMB treatment results from the inhibition of ACVR1-mediated hepcidin expression in the liver, increased mobilization of sequestered iron from cellular stores and subsequent stimulation of erythropoiesis.Here we demonstrate that MMB treatment in anemic rats resulted in a reduction of hepcidin and amelioration of anemia; whereas ruxolitinib dosing affected neither hepcidin nor anemia. Short-term MMB oral treatment in anemic rats resulted in a dose responsive inhibition of serum hepcidin induction with complete suppression at 25 mg/kg QD, 82% inhibition at 10 mg/kg QD, and 55% inhibition at 5 mg/kg QD (Table 1). Interestingly, only the two higher doses show significant time above EC50 levels, whereas the 5 mg/kg dose (which most closely approximates MMB human clinical exposures) only shows significant time above EC20. This suggests that systemic drug concentrations alone may not accurately predict activity in the model as 5 mg/kg demonstrated a 55% reduction in serum hepcidin. In a rat quantitative whole body autoradiography tissue distribution study, MMB levels have been demonstrated to be 3-4 fold higher in the liver relative to blood (Figure 1). Thus, the significant inhibiton of hepcidin levels in animals dosed with 5 mg/kg MMB may be due to higher concentrations in the liver. MMB concentrations would be expected to be higher in the liver relative to blood in humans as well.Our results provide preclinical evidence for a direct role of MMB in regulating iron homeostasis through the ACVR1/hepcidin axis. Evaluation of the activity of MMB on the ACVR1/hepcidin axis is being done in ongoing MMB clinical studies in patients with MF. [Display omitted] [Display omitted] DisclosuresWarr:Gilead Sciences: Employment, Equity Ownership. Zheng:Gilead Sciences: Employment, Equity Ownership. Sharma:Gilead Sciences: Employment, Equity Ownership. Maciejewski:Gilead Sciences: Employment, Equity Ownership. Theurl:Gilead Sciences: Research Funding. Whitney:Gilead Sciences: Employment, Equity Ownership.

Gene expression and silencing of activin receptor type 2A (ACVR2A) in myoblast cells of chicken

Activin receptor type 2A (ACVR2A) acts as receptor for myostatin (MSTN) protein involved in inhibiting satellite cell proliferation and differentiation. The importance of the ACVR2A gene during embryonic and post-hatch periods in broiler and layer chicken was studied in an in vitro cell culture system.The expression pattern of the ACVR2A gene during embryonic stages was similar in broiler and layer lines. Post-hatch expression of the ACVR2A gene varied significantly between broiler and layer lines.Five shRNA molecules were designed to knockdown expression of the ACVR2A gene in chicken myoblast cells. The silencing of the ACVR2A gene in a cell culture system varied from 60% to 82%.It is concluded that between broiler and layer lines, there were no significant changes in expression of the ACVR2A gene during embryonic stages but it varied significantly during the post-hatch period. The shRNA showed silencing of the ACVR2A gene under an in vitro cell culture system.

The Fibrodysplasia Ossificans Progressiva (FOP) mutation p.R206H in ACVR1 confers an altered ligand response

Patients with Fibrodysplasia Ossificans Progressiva (FOP) suffer from ectopic bone formation, which progresses during life and results in dramatic movement restrictions. Cause of the disease are point mutations in the Activin A receptor type 1 (ACVR1), with p.R206H being most common.In this study we compared the signalling responses of ACVR1WT and ACVR1R206H to different ligands. ACVR1WT, but not ACVR1R206H inhibited BMP signalling of BMP2 or BMP4 in a ligand binding domain independent manner. Likewise, the basal BMP signalling activity of the receptor BMPR1A or BMPR1B was inhibited by ACVR1WT, but enhanced by ACVR1R206H. In comparison, BMP6 or BMP7 activated ACVR1WT and caused a hyper-activation of ACVR1R206H. These effects were dependent on an intact ligand binding domain. Finally, the neofunction of Activin A in FOP was tested and found to depend on the ligand binding domain for activating ACVR1R206H. We conclude that the FOP mutation ACVR1R206H is more sensitive to a number of natural ligands. The mutant receptor apparently lost some essential inhibitory interactions with its ligands and co-receptors, thereby conferring an enhanced ligand-dependent signalling and stimulating ectopic bone formation as observed in the patients.

Ligand trap of the activin receptor type IIA inhibits osteoclast stimulation of bone remodeling in diabetic mice with chronic kidney disease

Dysregulation of skeletal remodeling is a component ofrenal osteodystrophy. Previously, we showed that activinreceptor signaling is differentially affected in various tissues in chronic kidney disease (CKD). We tested whether a ligand trap for the activin receptor type 2A (RAP-011) is an effective treatment of the osteodystrophy of the CKD-mineral bone disorder. With a 70% reduction inthe glomerular filtration rate, CKD was induced at 14weeks of age in the ldlr-/- high fat-fed mouse modelofatherosclerotic vascular calcification and diabetes. Twenty mice with CKD, hyperphosphatemia, hyperparathyroidism, and elevated activin A were treated with RAP-011, wherease 19 mice were given vehicle twice weekly from week 22 until the mice were killed at 28 weeks of age. The animals were then evaluated by skeletal histomorphometry, micro-computed tomography, mechanical strength testing, and exvivo bone cell culture. Results in the CKD groups were compared with those of the 16 sham-operated ldlr-/- high fat-fed mice. Sham-operated mice had low-turnover osteodystrophy and skeletal frailty. CKD stimulated bone remodeling with significant increases in osteoclast and osteoblast numbers and bone resorption. Compared with mice with CKD andsham-operated mice, RAP-011 treatment eliminated the CKD-induced increase in these histomorphometric parameters and increased trabecular bone fraction. RAP-011 significantly increased cortical bone area and thickness. Activin A-enhanced osteoclastogenesis was mediated through p-Smad2 association with c-fos and activation of nuclear factor of activated T cells c1 (NFATc1). Thus, an ActRIIA ligand trap reversed CKD-stimulated bone remodeling, likely through inhibition ofactivin-A induced osteoclastogenesis.

Muscle and Bone: Combating the Evil Side of the Connection.

Muscle and Bone: Combating the Evil Side of the Connection.

MiR-125b Regulates Primordial Follicle Assembly by Targeting Activin Receptor Type 2a in Neonatal Mouse Ovary.

The establishment of the primordial follicle pool is crucial for fertility in mammalian females, and the interruption of overall micro-RNA production byDicer1conditional knockout in the female reproductive system results in infertility. However, there are few reports about the functions of individual micro-RNA in regulating primordial follicle assembly. The present study aimed to investigate the function of miR-125b, which is conserved and preferentially expressed in mammalian ovary during primordial follicle assembly. Detection of miR-125b in the developing mouse ovaries by real-time PCR and in situ hybridization showed that it was highly expressed perinatally and specifically located in the ovarian somatic cells. MiR-125b overexpression blocked the process of primordial follicle assembly in cultured newborn mouse ovaries, while its knockdown promoted this process. Further studies showed that miR-125b regulated the activin/Smad2 signaling in neonatal mouse ovary by directly targeting the 3'-untranslated region of activin receptor type 2a (Acvr2a). Overexpression of miR-125b in neonatal mouse ovary suppressed theAcvr2aprotein level, attenuating activin/Smad2 signaling, while knockdown of miR-125b showed the opposite effects. In addition, recombinant human activin A (rh-ActA) down-regulated miR-125b in the neonatal mouse ovary. Overexpression of miR-125b attenuated the promoting effects of rh-ActA on primordial follicle assembly. Taken together, these data suggest that miR-125b blocks the process of primordial follicle assembly, and miR-125b may play this role by regulating the expression ofAcvr2ain the activin/Smad2 signaling pathway.

Generation of integration free induced pluripotent stem cells from fibrodysplasia ossificans progressiva (FOP) patients from urine samples

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare, autosomal dominant transmitted genetic disease. Patients experience progressive bone formation replacing tendons, ligaments, muscle and soft tissue. Cause of FOP are gain-of-function mutations in the Bone Morphogenetic Protein (BMP) receptor Activin A receptor type 1 (ACVR1) (Kaplan et al., 2008). The most common mutation is R206H, which leads to the substitution of codon 206 from arginine to histidine (Shore et al., 2006).Here, we describe the derivation and characterization of two hiPSC lines from two FOP patients, both carrying the mutation R206H. Cells were isolated from urine and reprogrammed using integration free Sendai virus vectors under defined conditions.

Activin receptor 2A and activin receptor 2B genes in chicken: effect on carcass traits

ABSTRACTCarcass traits are of immense importance in chicken as some parts of the carcass particularly breast muscle and legs are mostly preferred by the consumers with good market price while the remaining parts have a lower price. Carcass traits primarily depend on the growth of the birds, which are controlled by the candidate genes. Activin receptor type 2A and 2B act as receptors for binding with the members of transforming growth factor superfamily like myostatin to expedite its biological functions. We analysed exon2 and exon4 of activin receptor type 2A and 2B genes in six chicken populations. Both the genes revealed the presence of four haplotypes in these chicken populations. Association studies revealed a significant effect of genotypes and haplotypes on certain carcass traits such as carcass weight, dressing %, back and neck weight, giblet weights, etc. It is concluded that the exons of ACVR2A and ACVR2B genes were polymorphic and potentially associated with certain carcass traits in chicken.