A5011991717- Heterotopic Ossification and Related Conditions
- TGF-β signaling in diseases
- Bone Metabolism and Diseases
- Parathyroid Disorders and Treatments
- Lipid metabolism and biosynthesis
- Connective tissue disorders research
- Medical Imaging and Pathology Studies
- Microbial Natural Products and Biosynthesis
- Microbial Metabolic Engineering and Bioproduction
- Cholesterol and Lipid Metabolism
- Plant biochemistry and biosynthesis
- Enzyme Catalysis and Immobilization
- Axial and Atropisomeric Chirality Synthesis
- Alkaline Phosphatase Research Studies
- Carbohydrate Chemistry and Synthesis
- Chemical synthesis and alkaloids
- Cancer-related gene regulation
- Invertebrate Immune Response Mechanisms
- Bone health and treatments
- Alkaloids: synthesis and pharmacology
- Wnt/β-catenin signaling in development and cancer
- Peroxisome Proliferator-Activated Receptors
- Orthopaedic implants and arthroplasty
- Plant-derived Lignans Synthesis and Bioactivity
- Viral Infectious Diseases and Gene Expression in Insects
Kitasato University
2013-2025
Saitama Medical University
2009-2023
Harvard University
2013-2019
Boston University
2019
Smad1, Smad5 and Smad9 (also known as Smad8) are activated by phosphorylation bone morphogenetic protein (BMP)-bound type I receptor kinases. We examined the role of creating constitutively active forms (SmadDVD). Transcriptional activity Smad9DVD was lower than that Smad1DVD or Smad5DVD, even though all three SmadDVDs associated with Smad4 bound to target DNA. The linker region sufficient reduce transcriptional activity. expression increased activation BMP signaling, similar inhibitory...
Enhanced BMP or canonical Wnt (cWnt) signaling are therapeutic strategies employed to enhance bone formation and fracture repair, but the mechanisms each pathway utilizes specify cell fate of bone-forming osteoblasts remain poorly understood. Among all BMPs expressed in bone, we find that singular deficiency Bmp2 blocks ability cWnt from limb bud marrow progenitors. When exposed cWnts, Bmp2-deficient cells fail progress through Runx2/Osx1 checkpoint thus do not upregulate multiple genes...
Bone morphogenic proteins (BMPs) stimulate bone formation in vivo and osteoblast differentiation vitro via a Smad signaling pathway. Recent findings revealed that the activation of nuclear factor-κB (NF-κB) inhibits BMP-induced differentiation. Here, we show NF-κB BMP by directly targeting A selective inhibitor classic pathway, BAY11–770682, enhanced BMP2-induced ectopic vivo. In mouse embryonic fibroblasts (MEFs) prepared from mice deficient p65, main subunit NF-κB, BMP2, induced...
An alkaloid piperine isolated from the Piper Nigrum was found to inhibit lipid droplet accumulation in mouse macrophages, and especially inhibited cholesteryl ester (CE) synthesis (IC50: 25 microM). The metabolism of cholesterol lysosome with a similar IC50 (18 microM), indicating that site inhibition is one steps between lysosomes endoplasmic reticulum. Therefore, effects on acyl-CoA:cholesterol acyltransferase (ACAT) activity microsomes prepared macrophage liver were studied, show...
Two decades after signals controlling bone length were discovered, the endogenous ligands determining width remain unknown. We show that postnatal establishment of normal in mice, as mediated by bone-forming activity periosteum, requires BMP signaling at innermost layer periosteal niche. This developmental center becomes quiescent during adult life. Its reactivation however, is necessary for growth, enhanced strength, and accelerated fracture repair response to bone-anabolic therapies used...
Various substitution mutations in ALK2, a transmembrane serine/threonine kinase receptor for bone morphogenetic proteins (BMPs), have been identified patients with genetic disorders such as fibrodysplasia ossificans progressiva (FOP), diffuse intrinsic pontine glioma (DIPG) and heart defects. In this study, we characterized the ALK2 mutants R258G, G328V F246Y, which were severe FOP, DIPG unusual hereditary skeletal dysplasia, respectively. Both R258G gain-of-function mutations, but F246Y was...
Abstract Phosphorylation of Smad1/5/8 at carboxyl-terminal serine residues by type I receptors activates downstream bone morphogenetic protein (BMP) signaling. Protein phosphatase magnesium-dependent 1A (PPM1A) has been shown to suppress BMP activity dephosphorylating phospho-Smads. We report here that PPM1A suppresses signaling via a novel mechanism. inhibited constitutively activated Smad1 mutant lacking receptor phosphorylation sites. reduced the levels not only but also Smad5 and Smad8....
Abstract Atropisomeric dinapinones A1 and A2 (DPA1 DPA2) were isolated from a culture of Talaromyces pinophilus FKI‐3864. Monapinone coupling enzyme (MCE), which dimerizes naphthopyranone monapinone A (MPA), was purified cell‐free extract T. MCE regioselectively MPA at the 8,8′‐positions to synthesize atropisomers DPA1 DPA2 in ratio approximately 1:2.5 without cofactor. The optimal pH value temperature for 4.0 50 °C, apparent K m V max values (72.7±23.2) μ (1.21±0.170) μmol min −1 mg...
ABSTRACT Growth and differentiation factors (GDFs) are secreted signaling molecules within the BMP family that have critical roles in joint morphogenesis during skeletal development mice humans. Using genetic data obtained from a six-generation Chinese family, we identified missense variant GDF6 (NP_001001557.1; p.Y444N) fully segregates with novel autosomal dominant synostoses (SYNS) phenotype, which designate as SYNS4. Affected individuals display bilateral wrist ankle deformities at birth...
Bone morphogenetic proteins (BMPs) induce osteoblastic differentiation in myogenic cells via the phosphorylation of Smads. Two types Smad phosphatases--small C-terminal domain phosphatase 1 (SCP1) and protein magnesium-dependent 1A--have been shown to inhibit BMP activity. Here, we report that SCP1 inhibits induced by BMP-4, a constitutively active receptor, form Smad1. The activity was required for this suppression, knockdown myoblasts stimulated signaling. In contrast 1A, did not reduce...
Fibrodysplasia ossificans progressiva (FOP) is a genetic disorder characterized by progressive heterotopic ossification in soft tissues, such as the skeletal muscles. FOP has been shown to be caused gain-of-function mutations activin receptor-like kinase (ALK)-2, which type I receptor for bone morphogenetic proteins (BMPs). In present study, we examined molecular mechanisms that underlie activation of intracellular signaling mutant ALK2. Mutant ALK2 from patients enhanced II BMP receptors,...
Transducing‐like enhancer of split 3 (TLE3), one the Groucho/TLE family members, targets Runx2 transcription and suppresses osteoblast differentiation in bone marrow stromal cells (BMSCs). Here, we identify Wnt responsive elements TLE3 promoter region through comparative genomic functional analyses show that expression is increased by signaling, which important for differentiation. We also demonstrated able to suppress canonical signaling BMSCs. Taken together, our data suggest induction...
Abstract Mutations in activin receptor-like kinase 2 (ALK2) can cause the pathological osteogenic signaling seen some patients with fibrodysplasia ossificans progressiva and other conditions such as diffuse intrinsic pontine glioma. Here, we report that intracellular domain of wild-type ALK2 readily dimerizes response to BMP7 binding drive signaling. This is pathologically triggered by heterotetramers type II receptor kinases mutant forms, which form dimers A binding. We develop a blocking...
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant congenital disorder characterized by progressive heterotopic ossification in muscle tissues. A constitutively activated mutation of bone morphogenetic protein (BMP) receptor, ALK2, has been identified patients with FOP. We report here that four structurally related compounds, lucilactaene, hydroxylucilactaene, NG-391 and NG-393, produced fungal strain Fusarium sp. B88, inhibit BMP signaling vitro. Alkaline phosphatase...