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Articular Cartilage Development
Published in Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi, Articular Cartilage, 2017
Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi
It is noteworthy that BMP1 is not a member of the BMP family, but rather is a procollagen C-proteinase involved in the proteolytic processing of soluble procollagen, resulting in self-assembly of insoluble collagen fibers in the extracellular matrix (Reddi 1996).
Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Published in Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow, Fetal and Perinatal Skeletal Dysplasias, 2012
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow
Genetics: OI types 1–5 are inherited in an autosomal dominant manner and most are caused by mutations in the genes COL1A1 or COL1A2. Almost 60% of individuals with mild OI have de novo mutations (mutation detection rate in this group is 100%); virtually 100% of individuals with lethal (type 2) OI or with severe (type 3) OI have a de novo mutation (mutation detection rate in this group 60%–98%). Penetrance of COL1A1 or COL1A2 mutations is complete; expression can be variable. OI types 6–9 are inherited in an autosomal recessive manner, and caused by mutations in CRTAP (OI 7, and a small proportion of cases of OI 2/3), LEPRE (OI 8) and PPIB (OI 9). Mutations within these genes cause decreased collagen 3-prolyl hydroxylation. Recently, mutations in the genes FKBP10 and SERPINH1 have also been found as causing severe recessive forms of OI: both these genes encode for chaperone proteins whose deficiency causes impairment of type 1 procollagen folding and secretion. Recessive mutations in SERPINF1 have been associated with both OI type 3 and 6. SERPINF1 encodes for PEDF (pigment epithelium derived factor), the absence of which disturbs bone homeostasis independent of alterations in type I collagen synthesis or intracellular processing. BMP1 is a further gene resulting in autosomal recessive OI. OI types 6–9 may be grouped together as autosomal recessive OI.
Bone morphogenetic protein (BMP)9 in cancer development: mechanistic, diagnostic, and therapeutic approaches?
Published in Journal of Drug Targeting, 2023
Ali G. Alkhathami, Mustafa Ryadh Abdullah, Muhjaha Ahmed, Hanan Hassan Ahmed, Sarab W. Alwash, Zahra Muhammed Mahdi, Fahad Alsaikhan, Ayed A. Dera
According to similarities regarding amino acid sequences, BMPs are a family of at least 10 different proteins that belong to the TGF-β superfamily and play crucial roles in skeletal development and maintenance, including BMP1 to BMP15, of which BMP1 is a metalloprotease and is not considered a TGFβ member [7]. BMPs transduce their signals by binding to transmembrane serine-threonine kinase receptors (type I and type II receptors). There are four known BMP type I receptors (ALK1, ALK2, ALK3 (BMPRIA) and ALK6 (BMPRIB)) and three type II receptors (BMPR-II, ActR-IIA and ActR-IIB). The heterotetrameric receptor complexes consist of two molecules of type I and II receptors. Upon BMP binding to receptor complexes, type I receptors are phosphorylated and activated by type II receptors which consequently mediate phosphorylation of downstream signalling molecules, leading to the activation of cytoplasmic SMAD proteins [8]. Three classes of SMAD proteins, including receptor-regulated SMADs (R-SMADs, e.g. SMAD1, 5, and 8), the common mediator SMAD (Co-SMAD, e.g. SMAD4), inhibitory SMADs (I-SMADs, e.g. SMAD6 and 7) are involved in BMPR signalling. BMPs binding to the BMPRs results in SMAD4 translocation into the nucleus, which consequently activates transcription factors such as AP1, RUNX, bZIP, Fox, bHLH, Sp1, IRF7, and Homeodomain. Moreover, BMP may also employ SMAD-independent signalling through activating MAPKs such as ERK, JNK, or p38 MAPK [9].
Genome- and transcriptome-wide association studies show that pulmonary embolism is associated with bone-forming proteins
Published in Expert Review of Hematology, 2022
Ruoyang Feng, Mengnan Lu, Yanni Yang, Pan Luo, Lin Liu, Ke Xu, Peng Xu
First, we performed LDSC analysis of GWAS data for PE and 3283 human plasma proteins, and identified five plasma proteins that were genetically associated with PE; these included hydroxycarboxylic acid receptor 2, defensin 118, tendon-like protein 1, bone formation protein 7, and apolipoprotein 1. Then, we assessed GWAS data for PE using skeletal muscle and blood as gene expression reference guides with full transcriptome association. The genes associated with PE were identified and compared with the genes encoding the aforementioned five proteins, and the BMP genes were found to be the overlapping genes (BMP8B, BMP8A, BMP2K). Similarly, we compared the genes obtained for the five plasma proteins with the differentially expressed genes from PE and normal healthy patients and again found that the overlapping genes were those that encoded bone forming proteins (BMP7, BMP2K, BMPR2, BMPR1A, BMPR1B, BMP10, BMP6, BMP1, BMP8B, and BMP8A). The results obtained so far strongly suggest that bone forming proteins are involved in the development and pathogenesis of PE.
Synthesis and structure–activity relationships of pyrazole-based inhibitors of meprin α and β
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Kathrin Tan, Christian Jäger, Stefanie Geissler, Dagmar Schlenzig, Mirko Buchholz, Daniel Ramsbeck
Proteases are involved in numerous processes that regulate the proper function of organisms. An impaired function of proteases or a dysregulation of proteolytic networks could lead to the development of diseases. Thus, proteases have always been important and promising drug targets1. An important family of proteases are metalloproteases, in particular the metzincins. This family includes matrix metalloproteases (MMPs), disintegrin and metalloproteases (ADAMs), ADAMs with thrombospondin motifs (ADAMTSs), and the astacins. The latter comprises bone-morphogenetic protein 1 (BMP-1), ovastacin, and the meprins α and β in human2. However, unlike MMPs or ADAMs, astacins received only a little attention in drug discovery in the past. Nevertheless, continuously growing knowledge of astacin biology increases the evidence that they are potential drug targets as well. In particular, meprin α and β seem to be involved in the pathophysiology of various diseases. Thus, they emerged as promising drug targets during the last years. While meprin α is expressed as soluble homodimer, meprin β homodimers mainly remain membrane-bound, but can also be shed from the cell surface3,4. In tissues co-expressing both meprins, meprin α is also bound to the cell membrane via the formation of meprin α/β heterodimers5. These differences in expression and localisation also determine different cleavage specificities and thus different roles in health and disease.6,7 Meprin α is supposed to act as pro-migratory protease in the context of colorectal and hepatocytic cancer8–13 and was also linked to vascular diseases like arteriosclerosis, cardiac remodelling, and aneurysms, recently14–16. Meprin β is also involved in cancer cell invasion17,18 and moreover is able to act as an alternative beta-secretase, contributing to the progression of Alzheimer’s disease via the release of neurotoxic amyloid peptides4,19–23. Both proteases act as procollagenases and are involved in the biosynthesis and assembly of collagen fibrils. Hence, they are potentially involved in the development of fibrotic diseases, e.g. keloids or lung fibrosis24–26. Further substrates include different cytokines and components of the extracellular matrix, rendering meprin α and β potential drug targets in inflammatory or kidney diseases27–33.