Bone Morphogenetic Protein Receptor Research Articles

Drosophila Atlastin regulates synaptic vesicle mobilization independent of bone morphogenetic protein signaling

BackgroundThe endoplasmic reticulum (ER) contacts endosomes in all parts of a motor neuron, including the axon and presynaptic terminal, to move structural proteins, proteins that send signals, and lipids over long distances. Atlastin (Atl), a large GTPase, is required for membrane fusion and the structural dynamics of the ER tubules. Atl mutations are the second most common cause of Hereditary Spastic Paraplegia (HSP), which causes spasticity in both sexes’ lower extremities. Through an unknown mechanism, Atl mutations stimulate the BMP (bone morphogenetic protein) pathway in vertebrates and Drosophila. Synaptic defects are caused by atl mutations, which affect the abundance and distribution of synaptic vesicles (SV) in the bouton. We hypothesize that BMP signaling, does not cause Atl-dependent SV abnormalities in Drosophila.ResultsWe show that atl knockdown in motor neurons (Atl-KD) increases synaptic and satellite boutons in the same way that constitutively activating the BMP-receptor Tkv (thick veins) (Tkv-CA) increases the bouton number. The SV proteins Cysteine string protein (CSP) and glutamate vesicular transporter are reduced in Atl-KD and Tkv-CA larvae. Reducing the activity of the BMP receptor Wishful thinking (wit) can rescue both phenotypes. Unlike Tkv-CA larvae, Atl-KD larvae display altered activity-dependent distributions of CSP staining. Furthermore, Atl-KD larvae display an increased FM 1–43 unload than Control and Tkv-CA larvae. As decreasing wit function does not reduce the phenotype, our hypothesis that BMP signaling is not involved is supported. We also found that Rab11/CSP colocalization increased in Atl-KD larvae, which supports the concept that late recycling endosomes regulate SV movements.ConclusionsOur findings reveal that Atl modulates neurotransmitter release in motor neurons via SV distribution independently of BMP signaling, which could explain the observed SV accumulation and synaptic dysfunction. Our data suggest that Atl is involved in membrane traffic as well as formation and/or recycling of the late endosome.

The unique role of bone marrow adipose tissue in ovariectomy-induced bone loss in mice.

Accumulation of bone marrow adipose tissue (BMAT) is always seen in osteoporosis induced by estrogen deficiency. Herein, we aimed to investigate the mechanisms and consequences of this phenomenon by establishing a mouse model of osteoporosis caused by ovariectomy (OVX)-mimicked estrogen deficiency. Micro-CT, osmium tetroxide staining, and histological analyses were performed to examine the changes in bone microstructure, BMAT and white adipose tissue (WAT) in OVX mice compared to sham mice. The osteogenesis and adipogenesis of primary bone marrow stromal cells (BMSCs) isolated from sham and OVX mice were compared in vitro. The molecular phenotypes of BMAT and WAT were determined and compared by quantitative PCR (qPCR). Bone marrow adipocyte-conditioned medium (BMA CM) was prepared from sham or OVX mice for coculture assays, and BMSCs or bone marrow monocytes/macrophages (BMMs) were isolated and subjected to osteoblast and osteoclast differentiation, respectively. Cell staining and qPCR were used to assess the effects of BMAT on bone metabolism. OVX-induced estrogen deficiency induced reductions in both cortical and trabecular bone mass along with an expansion of BMAT volume. At the cellular level, loss of estrogen inhibited BMSC osteogenesis and promoted BMSC adipogenesis, whereas addition of estradiol exerted the opposite effects. In response to estrogen deficiency, despite the common proinflammatory molecular phenotype observed in both fat depots, BMAT, unlike WAT, unexpectedly exhibited an increase in adipocyte differentiation and lipolytic activity as well as the maintenance of insulin sensitivity. Importantly, BMAT, but not WAT, presented increased mRNA levels of both BMP receptor inhibitors (Grem1, Chrdl1) and Rankl following OVX. In addition, treatment with BMA CM, especially from OVX mice, suppressed the osteoblast differentiation of BMSCs while favoring the osteoclast differentiation of BMMs. Our study illustrates that OVX-induced estrogen deficiency results in bone loss and BMAT expansion by triggering imbalance between the osteogenesis and adipogenesis of BMSCs. Furthermore, expanded BMAT, unlike typical WAT, may negatively regulate bone homeostasis through paracrine inhibition of osteoblast-mediated bone formation and promotion of osteoclast-mediated bone resorption.

METTL3-induced lncRNA GBAP1 promotes hepatocellular carcinoma progression by activating BMP/SMAD pathway

BackgroundHepatocellular carcinoma (HCC) is one of the most common and challenging cancers in the world. N6-methyladenosine (m6A) modification and long non-coding RNAs (lncRNAs) play critical roles in the progression of HCC. However, there are few reports on genome-wide screening and functional annotations of m6A-methylated lncRNAs in HCC.MethodsThe expression levels of m6A methyltransferase METTL3 and the association with the prognosis in HCC were determined by RT-qPCR, public dataset platforms. Then, RNA-seq, Pearson correlation analysis, MeRIP-qPCR, RNA half-life assay, gene site-directed mutation, RIP assay and RT-qPCR analysis were employed to determine the downstream target of METTL3 in HCC. Subsequently, the expression levels and roles of lncRNA glucosylceramidase beta pseudogene 1 (GBAP1) in HCC were determined by Kaplan–meier curves, RT-qPCR, in vitro functional experiments and in vivo tumorigenesis and lung metastasis models. Then, the downstream target and pathway of GBAP1 were explored by GO biological process, KEGG pathway enrichment, luciferase reporter assay, RIP assay and rescue experiments and so on.ResultsMETTL3 was upregulated in HCC and closely related to HCC prognosis. And METTL3 induced GBAP1 expression by acting as the m6A writer of GBAP1 and IGF2BP2 worked as its m6A reader. Clinically, GBAP1 expression was significantly associated with tumor size, venous infiltration, TNM stage and prognosis of HCC, Functionally, GBAP1 promoted HCC metastasis and growth both in vitro and in vivo. Furthermore, GBAP1 acted as the molecular sponge for miR-22-3p to increase the expression of bone morphogenetic protein receptor type 1A (BMPR1A), which then activated BMP/SMAD pathway in HCC cells.ConclusionsOur findings demonstrated that METTL3-induced GBAP1 promoted migration, invasion and proliferation of HCC cells via GBAP1/miR-22-3p/BMPR1A/SMAD axis. GBAP1 could be a potential prognosis indicator and therapeutic target for HCC.

Investigation for Mutation in BMPR-1B (FecB) Fecundity Gene in Awassi Sheep

Reproduction related traits in sheep such as ovulation rate and litter size are traits of high economic importance but as these traits are only expressed in one sex and in mature animals, thus inclusion of them in selection strategies is limited. Therefore, studying genes associated with reproductive events provides genotypic data, which is more useful in genetic improvement of sheep in a short period of time. Such reproductive traits in sheep are genetically controlled by genes having both additive and major effects. Booroola is the first gene identified in Booroola Merino sheep in Australia has major effects on ewe’s reproduction and has gained much popularity in sheep breeding for its immense economic value. Booroola or Bone Morphogenetic Protein Receptor -1B (BMPR-1B) gene is in chromosome 6 and FecB allele is the result of a single mutation in this gene where one copy of this allele results in a significant increase in ovulation rate thus outcome as increased lambing per parturition. The Awassi sheep is an indigenous breed of Turkey and identifying major genes for fecundity could greatly improve their breeding program. To identify the FecB gene in Awassi sheep, 88 blood samples were taken, and DNA was extracted by salting out method. After PCR amplification and AvaΠ digestion, the samples were analyzed for FecB mutation and all of 88 samples were found not to carry the mutant allele (FecB).

GLIS3, a novel prognostic indicator of gastric adenocarcinoma, contributes to the malignant biological behaviors of tumor cells via modulating TGF-β1/TGFβR1/Smad1/5 signaling pathway

GLIS3 is highly expressed in multiple cancers, but it has not been studied in gastric adenocarcinoma (GAC). Based on bioinformatics analysis, the prognostic significance of GLIS3 in GAC was analyzed. GAC cells were transfected with small interfering (si)-GLIS3 and GLIS3 overexpression plasmid as well as treated with SB505124 [an inhibitor for transforming growth factor beta receptor 1 (TGFβR1)] and dorsomorphin [an inhibitor for bone morphogenetic protein receptor 1 (BMPR1)]. The GLIS3 expression was detected using qRT-PCR. The impacts of GLIS3 on the proliferation, invasion and migration of GAC cells were measured using cell function assays. The activation of phosphor (p)-Smad1/5 was tested by immunofluorescence. Western blot was utilized to measure the level of transforming growth factor (TGF)-β1/Smad1/5 signaling pathway-related proteins (TGF-β1, p-Smad1, Smad1, p-Smad5, Smad5). GLIS3 was expressed at high levels in GAC tissues and cell lines and its high expression could indicate the poor prognosis of GAC patients. GLIS3 inhibition declined the proliferative, invasive and migratory capabilities as well as TGF-β1 expression and phosphorylation of Smad1/5 in GAC cells. Overexpressed GLIS3 promoted proliferation, migration, invasion, TGF-β1 expression and Smad1/5 phosphorylation in GAC cells, with SB505124 reversing the effects of overexpressed GLIS3 on proliferation, migration, invasion and Smad1/5 phosphorylation whereas dorsomorphin exhibiting no influence on GLIS3-induced effects. GLIS3 facilitated the malignant phenotype of GAC cells via regulating TGF-β1/TGFβR1/Smad1/5 pathway, which may be a novel prognostic indicator of GAC and provided a target for GAC treatment.

Recommendations for the healthcare of patients with FOP

Fibrodysplasia ossificans progressiva (FOP) is avery rare, severe genetic disorder triggered by again-of-function mutation in the ACVR1 gene that codes for the typeI bone morphogenetic protein (BMP) receptor ACVR1 (activinAreceptor-type1), also known as ALK2 (activin receptor-like kinase-2). It leads to the onset and progression of heterotopic ossification (HO) in soft and connective tissue. HO is often preceded by episodes of soft tissue swelling or flare-ups. Flare-ups, characteristic of FOP, may be induced by trauma, infection, vaccination, or other medications, as well as surgical procedures or may occur spontaneously. As patients age, they develop severe mobility limitations due to progressive HO formation, including immobility, causing ashortened life expectancy. FOP's first characteristic clinical sign is the congenital malformation of one or both big toes with valgus axis deviation, which is present in almost all patients. To confirm the diagnosis, molecular genetic analysis of the ACVR1 gene is possible. This white paper aims to provide an overview of the necessary prerequisites and conditions for the care of patients with FOP and positively contribute to patients with FOP by improving the overall availability of knowledge. To achieve this, relevant aspects of the care of the very rare disease FOP are presented, from the initial diagnosis to the care in regular care based on the authors' knowledge (German FOP network) and the international FOP Treatment Guidelines. The recommendations presented here are addressed to all actors and decision-makers in the health care system and are also intended to inform patients and the public.

Sex-biased TGFβ signaling in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare cardiovascular disorder leading to pulmonary hypertension and, often fatal, right heart failure. Sex-differences in PAH are evident, which primarily presents with a female predominance and increased male severity. Disturbed transduction of the transforming growth factor-β (TGFβ) signaling family and gene mutations in the Bone morphogenetic protein receptor 2 (BMPR2) are risk factors for PAH development, but how sex-specific cues affect the TGFβ signaling family in PAH remains poorly understood. In this review we aim to explore the sex-bias in PAH by examining sex-differences in the TGFβ signaling family through mechanistical and translational evidence. Sex-hormones including estrogens, progestogens and androgens, can determine the expression of receptors (including BMPR2), ligands and soluble antagonists within the TGFβ family in a tissue-specific manner. Furthermore, sex-related genetic processes, i.e. Y-chromosome expression and X-chromosome inactivation, can influence the TGFβ signaling family at multiple levels. Given the clinical and mechanistical similarities, we expect that the conclusions arising from this review may apply also to hereditary hemorrhagic telangiectasia (HHT), a rare vascular disorder affecting the TGFβ signaling family pathway. In summary, we anticipate that investigating the TGFβ signaling family in a sex-specific manner will contribute to further understand the underlying processes leading to PAH and likely HHT.

Pharmacology and Rationale for Seralutinib in the Treatment of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a complex disorder characterized by vascular remodeling and a consequent increase in pulmonary vascular resistance. The histologic hallmarks of PAH include plexiform and neointimal lesions of the pulmonary arterioles, which are composed of dysregulated, apoptosis-resistant endothelial cells and myofibroblasts. Platelet-derived growth factor receptors (PDGFR) α and β, colony stimulating factor 1 receptor (CSF1R), and mast/stem cell growth factor receptor kit (c-KIT) are closely related kinases that have been implicated in PAH progression. In addition, emerging data indicate significant crosstalk between PDGF signaling and the bone morphogenetic protein receptor type 2 (BMPR2)/transforming growth factor β (TGFβ) receptor axis. This review will discuss the importance of the PDGFR-CSF1R-c-KIT signaling network in PAH pathogenesis, present evidence that the inhibition of all three nodes in this kinase network is a potential therapeutic approach for PAH, and highlight the therapeutic potential of seralutinib, currently in development for PAH, which targets these pathways.

Polymorphism studies and candidate genes associated with litter size traits in Indonesian goats. a systematic review

Background: Litter size (LS) is a significant, challenging, and economical aspect of the goat industry in Indonesia. It is influenced by several different factors and genes; consequently, identifying potential genes and loci associated with litter size has become a genetic problem. Several genetic indicators have been found to be associated with litter size in goats. This has prompted the need to discuss candidate genes associated with litter size in goats in Indonesia. Methods: A systematic review was conducted using critical databases including ResearchGate, Google Scholar, PubMed, Google search engine and Science direct. There were any exclusion criteria, they were as follows: articles published in languages other than English, Conference papers, short communication papers and papers not related to animals. After reviewing the abstracts of 42 publications, the remaining 17 investigations were chosen for full paper evaluation. A further eight studies were removed after a comprehensive evaluation of the publications because they did not match our inclusion criteria. Results: These markers include growth differentiation factor 9 (GDF9), bone morphogenetic protein 15 (BMP15), bone morphogenetic protein receptor type IB (BMPR1B), and kisspeptin (KISS1). Single nucleotide polymorphisms in these genes contribute to the development of novel genetic markers that helps in the selection of goats with the most favorable genotypes for litter size. This type of genetic selection is more successful than the traditional way of selecting animals for reproductive traits, particularly litter size. Conclusions: As a result, this study summarizes the genetic impacts of polymorphisms in candidate genes associated with litter size features in Indonesian goats.

Hsa-miR-27b-5p suppresses the osteogenic and odontogenic differentiation of stem cells from human exfoliated deciduous teeth via targeting BMPR1A: An ex vivo study.

Recently, miR-27b-5p was shown to be abundantly expressed in extracellular vehicles (EVs) from the inflammatory microenvironment. This study determined the role of miR-27b-5p in regulating osteogenic and odontogenic differentiation of stem cells from human exfoliated deciduous teeth (SHEDs) and further examined the regulatory mechanism of bone morphogenetic protein receptor type-1A (BMPR1A). Characteristics of SHEDs and SHEDs-EVs derived from SHEDs were evaluated respectively. The expression of miR-27b-5p in SHEDs and EVs was detected during osteo-induction. Mechanically, SHEDs were treated with miR-27b-5p mimics or an inhibitor, and the osteogenic/odontogenic differentiation and proliferation were assessed. Bioinformatic analysis and luciferase reporter were utilized for target gene prediction and verification. Finally, BMPR1A-overexpressed plasmids were transfected into SHEDs to investigate the participation of the BMPR1A/SMAD4 pathway. Data were analyzed by Student's t- test, One-way analysis of variance and Chi-square test. MiR-27b-5p was expressed in both SHEDs and EVs and was significantly increased at the initial stage of differentiation and then decreased in a time-dependent manner (p < .01). Upregulation of miR-27b-5p significantly suppressed osteogenic/odontogenic differentiation of SHEDs and inhibited proliferation (p < .05). Whereas inhibition of miR-27b-5p enhanced the differentiation (p < .05). Dual luciferase reporter assay and pull-down assay confirmed the binding site between miR-27b-5p and BMPR1A (p < .05). The overexpression of BMPR1A rescued the effect of miR-27b-5p, while contributed to the decrease of pluripotency (p < .05). Additionally, miR-27b-5p maintained pluripotency in BMPR1A-overexpressed SHEDs (p < .05). MiR-27b-5p in SHEDs/EVs was inversely associated with differentiation and suppressed the osteogenic and odontogenic differentiation of SHEDs and maintained the pluripotency of SHEDs partly by shuttering BMPR1A-targeting BMP signaling. Theoretically, inhibition of miR-27b-5p represents a potential strategy to promote osteanagenesis and dentinogenesis. However, miR-27b-5p capsuled EVs might maintain cell pluripotency and self-renewal for non-cell-targeted therapy.

Elevated BMPR2 expression amplifies osteoblast differentiation in ankylosing spondylitis.

Bone morphogenetic protein receptor type 2 (BMPR2) has been associated with radiographic changes in ankylosing spondylitis (AS), but further characterization of the cellular signaling pathway in osteoprogenitor (OP) is not clearly understood. The aim of this study was to investigate the expression of BMPR2 and bone morphogenetic protein 2 (BMP2)-mediated responsibility in AS. We collected 10 healthy control (HC) and 14 AS-OPs derived from facet joints. Subsequently, we then conducted RNA sequencing with two samples per group and selected BMP-related genes. Facet joint tissues and derived primary OPs were evaluated by validation of selected RNA sequencing data, immunohistochemistry, and comparison of osteogenic differentiation potential. Based on RNA-sequencing analysis, we found that BMPR2 expression is higher in AS-OPs compared to in HC-OPs. We also validated the increased BMPR2 expression in facet joint tissues with AS and its derived OPs in messenger RNA and protein levels. Additionally, primary AS-OPs showed much greater response to osteogenic differentiation induced by BMP2 and a higher capacity for smad1/5/8-induced RUNX2 expression compared to HCs. The expression of BMPR2 was found to be significantly increased in facet joint tissues of patients with AS. These findings suggest that BMPR2 may play a role in the BMP2-mediated progression of AS.

Polymorphism of the BMP-15 locus in Romanov sheep in Western Siberia

Currently, selective selection takes into account gene polymorphisms associated not only with multiple pregnancies (growth differentiation factor 9 (GDF-9), bone morphogenetic protein receptor (BMPR-IB), etc.) but also with milk parameters (β-lactoglobulin (β-lg), αS1-casein) and meat (myostatin (MSTN), calpastatin (CAST), calpain (CAPN1)) productivity. Thus, genes associated with the transforming growth factor began to be monitored to improve reproductive performance in sheep breeding: BMP-15, GDF-9, and BMPR-IB. Genetic markers related to animal reproduction are exciting, with several productive indicators and other evaluation criteria that have not been previously studied. Work on the relationship of animal gene inheritance with biochemical, haematological, environmental and zootechnical indicators is particularly relevant. In this paper, we consider genotypic variability in Romanov sheep for the BMP-15 gene locus, which belongs to the genes of the β-growth factor family. The distribution of genotypes in sheep of the Romanov breed in the conditions of Western Siberia was as follows: for ewes, the frequencies of genotypes WW–25%, WM–75, and MM–0%; for sheep - 0, 80 and 20%, respectively. All three genotypes (WW, WM, and MM) were identified in the studied sheep. The results differ from the data obtained in several other works on foreign sheep breeds (short-tailed sheep Khan, Awassi, Barki, Ossimi, Rahmani, etc.). It is interesting to study the BMP-15 locus further to establish its associations with biochemical and haematological parameters and the hormonal status of sheep.

Terminal differentiation of villus tip enterocytes is governed by distinct Tgfβ superfamily members.

The protective and absorptive functions of the intestinal epithelium rely on differentiated enterocytes in the villi. The differentiation of enterocytes is orchestrated by sub-epithelial mesenchymal cells producing distinct ligands along the villus axis, in particular Bmps and Tgfβ. Here, we show that individual Bmp ligands and Tgfβ drive distinct enterocytic programs specific to villus zonation. Bmp4 is expressed from the centre to the upper part of the villus and activates preferentially genes connected to lipid uptake and metabolism. In contrast, Bmp2 is produced by villus tip mesenchymal cells and it influences the adhesive properties of villus tip epithelial cells and the expression of immunomodulators. Additionally, Tgfβ induces epithelial gene expression programs similar to those triggered by Bmp2. Bmp2-driven villus tip program is activated by a canonical Bmp receptor type I/Smad-dependent mechanism. Finally, we establish an organoid cultivation system that enriches villus tip enterocytes and thereby better mimics the cellular composition of the intestinal epithelium. Our data suggest that not only a Bmp gradient but also the activity of individual Bmp drives specific enterocytic programs.

Bioinformatics Analysis of the Genetic and Epigenetic Alterations of Bone Morphogenetic Protein Receptors in Metastatic Breast Cancer.

The leading cause of mortality in patients with breast cancer is metastasis, and bone morphogenetic protein (BMP) signaling activation regulates metastasis in breast cancer. This study explored the genetic and epigenetic modification of BMP receptor genes associated with metastatic breast cancer cells using bioinformatics. The genetic and epigenetic alterations of BMP receptors (BMPR1A, BMPR1B, BMPR2, ACVR2A, ACVR1, ACVR2B, ACVR1B, HJV, and ENG) were examined using cBioportal and methSurv, respectively. mRNA expression was analyzed using TNM plot and bcgenex, and protein expression was studied using Human Protein Atlas. Prognostic value and ROC were investigated using Kaplan-Meier (KM) and ROC plot, respectively. Finally, mutant function was predicted using several databases, including PolyPhen-2, FATHMM, Mutation Assessor, and PredictSNP. Oncoprint analysis showed genetic alterations in BMPR1A (39%), BMPR1B (13%), BMPR2 (34%), ACVR2A (14%), ACVR1 (7%), ACVR2B (13), ACVR1B (35%), HJV (40%), and ENG (33%) across the patients with breast cancer in The Metastatic Breast Cancer Project. The mRNA and protein levels of BMPR2 were increased in metastatic breast tumor tissues compared with those in normal and breast tumor tissues. BMPR1A and BMPR2 showed the highest and lowest levels of epigenetic alterations among the BMP receptors, respectively. The patients with breast cancer who had low levels of BMPR2 had a better overall survival (OS) than those with high levels of BMPR2. Functional mutation prediction showed that mutants in BMPR2 (R272L, E274K, and L685F), ACVR2A (S127L), and ACVR1B (R484H), are deleterious, probably damaging, and possess a cancer phenotype. ROC plot revealed no BMP receptors correlated with endocrine therapy sensitivity. BMPR1B, BMPR2, and ACVR2A levels were significantly linked as moderate prediction of anti-HER2, BMPR2, and ACVR1B demonstrated moderate predictive potential for chemotherapy sensitivity. This study contributed in fully comprehending the significance of genetic and epigenetic alterations in BMP receptors and BMP signaling in metastatic breast cancer cells for the development of breast cancer treatment plans.

Pulmonary arterial hypertension in a pedigree with bone morphogenetic protein receptor 2 c.282 mutation

Pulmonary arterial hypertension in a pedigree with bone morphogenetic protein receptor 2 c.282 mutation

Reduced GS Domain Serine/Threonine Requirements of Fibrodysplasia Ossificans Progressiva Mutant Type I BMP Receptor ACVR1 in the Zebrafish.

Fibrodysplasia ossificans progressiva (FOP) is a rare human genetic condition characterized by altered skeletal development and extraskeletal bone formation. All cases of FOP are caused by mutations in the type I bone morphogenetic protein (BMP) receptor gene ACVR1 that result in overactivation of the BMP signaling pathway. Activation of the wild-type ACVR1 kinase requires assembly of a tetrameric type I and II BMP receptor complex followed by phosphorylation of the ACVR1 GS domain by type II BMP receptors. Previous studies showed that the FOP-mutant ACVR1-R206H required type II BMP receptors and presumptive glycine/serine-rich (GS) domain phosphorylation for overactive signaling. Structural modeling of the ACVR1-R206H mutant kinase domain supports the idea that FOP mutations alter the conformation of the GS domain, but it is unclear how this leads to overactive signaling. Here we show, using a developing zebrafish embryo BMP signaling assay, that the FOP-mutant receptors ACVR1-R206H and -G328R have reduced requirements for GS domain phosphorylatable sites to signal compared to wild-type ACVR1. Further, ligand-independent and ligand-dependent signaling through the FOP-mutant ACVR1 receptors have distinct GS domain phosphorylatable site requirements. ACVR1-G328R showed increased GS domain serine/threonine requirements for ligand-independent signaling compared to ACVR1-R206H, whereas it exhibited reduced serine/threonine requirements for ligand-dependent signaling. Remarkably, while ACVR1-R206H does not require the type I BMP receptor partner, Bmpr1, to signal, a ligand-dependent GS domain mutant of ACVR1-R206H could signal independently of Bmpr1 only when Bmp7 ligand was overexpressed. Of note, unlike human ACVR1-R206H, the zebrafish paralog Acvr1l-R203H does not show increased signaling activity. However, in domain-swapping studies, the human kinase domain, but not the human GS domain, was sufficient to confer overactive signaling to the Acvr1l-R203H receptor. Together these results reflect the importance of GS domain activation and kinase domain functions in regulating ACVR1 signaling and identify mechanisms of reduced regulatory constraints conferred by FOP mutations. © 2023 American Society for Bone and Mineral Research (ASBMR).

Multiple roles of ALK3 in osteoarthritis.

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by progressive cartilage degradation, synovial membrane inflammation, osteophyte formation, and subchondral bone sclerosis. Pathological changes in cartilage and subchondral bone are the main processes in OA. In recent decades, many studies have demonstrated that activin-like kinase 3 (ALK3), a bone morphogenetic protein receptor, is essential for cartilage formation, osteogenesis, and postnatal skeletal development. Although the role of bone morphogenetic protein (BMP) signalling in articular cartilage and bone has been extensively studied, many new discoveries have been made in recent years around ALK3 targets in articular cartilage, subchondral bone, and the interaction between the two, broadening the original knowledge of the relationship between ALK3 and OA. In this review, we focus on the roles of ALK3 in OA, including cartilage and subchondral bone and related cells. It may be helpful to seek more efficient drugs or treatments for OA based on ALK3 signalling in future.

PCTAIRE Protein Kinase 1 (PCTK1) Suppresses Proliferation, Stemness, and Chemoresistance in Colorectal Cancer through the BMPR1B-Smad1/5/8 Signaling Pathway.

Colorectal cancer (CRC) is the third most common cancer and a leading cause of cancer-related mortality worldwide. Even with advances in therapy, CRC mortality remains high. Therefore, there is an urgent need to develop effective therapeutics for CRC. PCTAIRE protein kinase 1 (PCTK1) is an atypical member of the cyclin-dependent kinase (CDK) family, and the function of PCTK1 in CRC is poorly understood. In this study, we found that patients with elevated PCTK1 levels had a better overall survival rate in CRC based on the TCGA dataset. Functional analysis also showed that PCTK1 suppressed cancer stemness and cell proliferation by using PCTK1 knockdown (PCTK1-KD) or knockout (PCTK1-KO) and PCTK1 overexpression (PCTK1-over) CRC cell lines. Furthermore, overexpression of PCTK1 decreased xenograft tumor growth and knockout of PCTK1 significantly increased in vivo tumor growth. Moreover, knockout of PCTK1 was observed to increase the resistance of CRC cells to both irinotecan (CPT-11) alone and in combination with 5-fluorouracil (5-FU). Additionally, the fold change of the anti-apoptotic molecules (Bcl-2 and Bcl-xL) and the proapoptotic molecules (Bax, c-PARP, p53, and c-caspase3) was reflected in the chemoresistance of PCTK1-KO CRC cells. PCTK1 signaling in the regulation of cancer progression and chemoresponse was analyzed using RNA sequencing and gene set enrichment analysis (GSEA). Furthermore, PCTK1 and Bone Morphogenetic Protein Receptor Type 1B (BMPR1B) in CRC tumors were negatively correlated in CRC patients from the Timer2.0 and cBioPortal database. We also found that BMPR1B was negatively correlated with PCTK1 in CRC cells, and BMPR1B expression was upregulated in PCTK1-KO cells and xenograft tumor tissues. Finally, BMPR1B-KD partially reversed cell proliferation, cancer stemness, and chemoresistance in PCTK1-KO cells. Moreover, the nuclear translocation of Smad1/5/8, a downstream molecule of BMPR1B, was increased in PCTK1-KO cells. Pharmacological inhibition of Smad1/5/8 also suppressed the malignant progression of CRC. Taken together, our results indicated that PCTK1 suppresses proliferation and cancer stemness and increases the chemoresponse of CRC through the BMPR1B-Smad1/5/8 signaling pathway.

Is sotatercept, which traps activins and growth differentiation factors, a new dawn in treating pulmonary arterial hypertension (PAH)?

ABSTRACT Introduction Although the prevalence of pulmonary arterial hypertension (PAH) is low, mortality is high. In PAH, there is a down-regulation of the bone morphogenetic protein receptor type 2 pathway, leading to a prominence of the upregulation pathway that is mediated by activins and growth differentiation factors acting at the receptor type IIA (ActRIIA). Sotatercept is an ActRIIA fusion protein. STELLAR was a phase 3 study of sotatercept for the treatment of PAH. Areas covered STELLAR. The primary endpoint of STELLAR was change from baseline at 24 weeks in the 6-minute walking distance, which was increased by 34.4 m by sotatercept compared to 1 m in the placebo group. Epistaxis/nosebleed, telangiectasia, and dizziness were more common with sotatercept than placebo. Expert opinion By targeting the remodeling in PAH, sotatercept is providing a new approach to the treatment of PAH and has the potential to slow or reverse cardiovascular remodeling in other conditions, e.g. left heart failure. However, the development of sotatercept for the treatment of PAH still requires a consideration of the appropriate dose and a longer-term assessment of the benefits and safety. If sotatercept becomes available for self-administration, it will be of interest to assess whether this affects adherence and benefits.

Cationic proteins from eosinophils bind bone morphogenetic protein receptors promoting vascular calcification and atherogenesis.

Blood eosinophil count and eosinophil cationic protein (ECP) concentration are risk factors of cardiovascular diseases. This study tested whether and how eosinophils and ECP contribute to vascular calcification and atherogenesis. Immunostaining revealed eosinophil accumulation in human and mouse atherosclerotic lesions. Eosinophil deficiency in ΔdblGATA mice slowed atherogenesis with increased lesion smooth muscle cell (SMC) content and reduced calcification. This protection in ΔdblGATA mice was muted when mice received donor eosinophils from wild-type (WT), Il4-/-, and Il13-/- mice or mouse eosinophil-associated-ribonuclease-1 (mEar1), a murine homologue of ECP. Eosinophils or mEar1 but not interleukin (IL) 4 or IL13 increased the calcification of SMC from WT mice but not those from Runt-related transcription factor-2 (Runx2) knockout mice. Immunoblot analyses showed that eosinophils and mEar1 activated Smad-1/5/8 but did not affect Smad-2/3 activation or expression of bone morphogenetic protein receptors (BMPR-1A/1B/2) or transforming growth factor (TGF)-β receptors (TGFBR1/2) in SMC from WT and Runx2 knockout mice. Immunoprecipitation showed that mEar1 formed immune complexes with BMPR-1A/1B but not TGFBR1/2. Immunofluorescence double-staining, ligand binding, and Scatchard plot analysis demonstrated that mEar1 bound to BMPR-1A and BMPR-1B with similar affinity. Likewise, human ECP and eosinophil-derived neurotoxin (EDN) also bound to BMPR-1A/1B on human vascular SMC and promoted SMC osteogenic differentiation. In a cohort of 5864 men from the Danish Cardiovascular Screening trial and its subpopulation of 394 participants, blood eosinophil counts and ECP levels correlated with the calcification scores of different arterial segments from coronary arteries to iliac arteries. Eosinophils release cationic proteins that can promote SMC calcification and atherogenesis using the BMPR-1A/1B-Smad-1/5/8-Runx2 signalling pathway.