RESUMO
PURPOSE OF REVIEW: Osteogenesis imperfecta or 'brittle bone disease' has mainly been considered a bone disorder caused by collagen mutations. Within the last decade, however, a surge of genetic discoveries has created a new paradigm for osteogenesis imperfecta as a collagen-related disorder, where most cases are due to autosomal dominant type I collagen defects, while rare, mostly recessive, forms are due to defects in genes whose protein products interact with collagen protein. This review is both timely and relevant in outlining the genesis, development, and future of this paradigm shift in the understanding of osteogenesis imperfecta. RECENT FINDINGS: Bone-restricted interferon-induced transmembrane (IFITM)-like protein (BRIL) and pigment epithelium-derived factor (PEDF) defects cause types V and VI osteogenesis imperfecta via defective bone mineralization, while defects in cartilage-associated protein (CRTAP), prolyl 3-hydroxylase 1 (P3H1), and cyclophilin B (CYPB) cause types VII-IX osteogenesis imperfecta via defective collagen post-translational modification. Heat shock protein 47 (HSP47) and FK506-binding protein-65 (FKBP65) defects cause types X and XI osteogenesis imperfecta via aberrant collagen crosslinking, folding, and chaperoning, while defects in SP7 transcription factor, wingless-type MMTV integration site family member 1 (WNT1), trimeric intracellular cation channel type b (TRIC-B), and old astrocyte specifically induced substance (OASIS) disrupt osteoblast development. Finally, absence of the type I collagen C-propeptidase bone morphogenetic protein 1 (BMP1) causes type XII osteogenesis imperfecta due to altered collagen maturation/processing. SUMMARY: Identification of these multiple causative defects has provided crucial information for accurate genetic counseling, inspired a recently proposed functional grouping of osteogenesis imperfecta types by shared mechanism to simplify current nosology, and has prodded investigations into common pathways in osteogenesis imperfecta. Such investigations could yield critical information on cellular and bone tissue mechanisms and translate to new mechanistic insight into clinical therapies for patients.
Assuntos
Mutação , Osteogênese Imperfeita/genética , Osteogênese Imperfeita/patologia , Antígenos de Diferenciação/genética , Proteína Morfogenética Óssea 1/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Ciclofilinas/genética , Proteínas da Matriz Extracelular/genética , Proteínas do Olho/genética , Proteínas de Choque Térmico HSP47/genética , Humanos , Canais Iônicos/genética , Glicoproteínas de Membrana/genética , Proteínas de Membrana/genética , Chaperonas Moleculares , Fatores de Crescimento Neural/genética , Proteínas do Tecido Nervoso/genética , Osteogênese/genética , Prolil Hidroxilases , Proteoglicanas/genética , Serpinas/genética , Fator de Transcrição Sp7 , Proteínas de Ligação a Tacrolimo/genética , Fatores de Transcrição/genética , Proteína Wnt1/genéticaRESUMO
Collagens V and XI comprise a single regulatory type of fibril-forming collagen with multiple isoforms. Both co-assemble with collagen I or II to form heterotypic fibrils and have been implicated in regulation of fibril assembly. The objective of this study was to determine the roles of collagens V and XI in the regulation of tendon fibrillogenesis. Flexor digitorum longus tendons from a haplo-insufficient collagen V mouse model of classic Ehlers Danlos syndrome (EDS) had decreased biomechanical stiffness compared with controls consistent with joint laxity in EDS patients. However, fibril structure was relatively normal, an unexpected finding given the altered fibrils observed in dermis and cornea from this model. This suggested roles for other related molecules, i.e. collagen XI, and compound Col5a1(+/-),Col11a1(+/-) tendons had altered fibril structures, supporting a role for collagen XI. To further evaluate this, transcript expression was analyzed in wild type tendons. During development (E18-P10) both collagen V and XI were comparably expressed; however, collagen V predominated in mature (P30) tendons. The collagens had a similar expression pattern. Tendons with altered collagen V and/or XI expression (Col5a1(+/-); Col11a1(+/-); Col5a1(+/-),Col11a1(+/-); Col11a1(-/-); Col5a1(+/-),Col11a1(-/-)) were analyzed at E18. All genotypes demonstrated a reduced fibril number and altered structure. This phenotype was more severe with a reduction in collagen XI. However, the absence of collagen XI with a reduction in collagen V was associated with the most severe fibril phenotype. The data demonstrate coordinate roles for collagens V and XI in the regulation of fibril nucleation and assembly during tendon development.
Assuntos
Colágeno Tipo V/metabolismo , Colágeno Tipo XI/metabolismo , Síndrome de Ehlers-Danlos/metabolismo , Tendões/crescimento & desenvolvimento , Tendões/metabolismo , Animais , Colágeno Tipo V/genética , Colágeno Tipo V/ultraestrutura , Colágeno Tipo XI/genética , Colágeno Tipo XI/ultraestrutura , Modelos Animais de Doenças , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/patologia , Humanos , Camundongos , Camundongos KnockoutRESUMO
Tendon fibroblasts synthesize and assemble collagen fibrils, the basic structural unit of tendons. Regulation of fibrillogenesis is essential for tendon development and function. Fibril assembly begins within extracellular micro-domains associated with the fibroblast surface. We hypothesize that molecules crucial to the regulation of fibril assembly are membrane associated and/or within the pericellular micro-environment. This report defines proteins in the surfaceome, that is, plasma membrane and pericellular matrix, from mouse flexor digitorum longus tendons. Proteomic analysis identified a set of surfaceome molecules including collagens, fibronectin, integrins, proteoglycans, and receptors in extracts from mouse tendons at postnatal day 1, a developmental stage when collagen protofibril nucleation and initial steps in fibril assembly predominate. The proteomic results were validated for molecules identified with a small number of unique peptides and/or low sequence coverage. For these analyses, proteins were selected based on their potential roles in fibril nucleation, that is, collagen V; organization of fibrillogenesis, that is, integrins and fibronectin; and known localization to the plasma membrane with potential to impact matrix assembly, that is, CD44, syndecan-1, epidermal growth factor receptor, and matrix metalloproteinase 25. These molecules were all detected in extracts of the developing tendon, demonstrating that the surfaceome included molecules hypothesized to regulate fibrillogenesis as well as many with no known function in this capacity. This report, therefore, generates an unbiased set of cell surface-associated molecules, providing a resource to identify novel or unexpected regulatory molecules involved in collagen fibril and matrix assembly.
Assuntos
Proteínas da Matriz Extracelular/metabolismo , Proteômica/métodos , Tendões/crescimento & desenvolvimento , Tendões/metabolismo , Animais , Membrana Celular/metabolismo , Cromatografia Líquida , Colágeno/metabolismo , Matriz Extracelular/metabolismo , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Anotação de Sequência MolecularRESUMO
Fibroblast growth factor (FGF)-2 regulates chondrocyte proliferation in the growth plate. Heparan sulfate (HS) proteoglycans bind FGF-2. Perlecan, a heparan sulfate proteoglycan (HSPG) in the developing growth plate, however, contains both HS and chondroitin sulfate (CS) chains. The binding of FGF-2 to perlecan isolated from the growth plate was evaluated using cationic filtration (CAF) and immunoprecipitation (IP) assays. FGF-2 bound to perlecan in both the CAF and IP assays primarily via the HS chains on perlecan. A maximum of 123 molecules of FGF-2 was calculated to bind per molecule of perlecan. When digested with chondroitinase ABC to remove its CS chains, perlecan augmented binding of FGF-2 to the FGFR-1 and FGFR-3 receptors and also increased FGF-2 stimulation of [(3)H]-thymidine incorporation in BaF3 cells expressing these FGF receptors. These data show that growth plate perlecan binds to FGF-2 by its HS chains but can only deliver FGF-2 to FGF receptors when its CS chains are removed.
Assuntos
Sulfatos de Condroitina/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Lâmina de Crescimento/química , Proteoglicanas de Heparan Sulfato/metabolismo , Heparitina Sulfato/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Animais , Bovinos , Condroitinases e Condroitina Liases/metabolismo , Proteoglicanas de Heparan Sulfato/química , Humanos , Polissacarídeo-Liases/metabolismoRESUMO
Fibroblast growth factor-18 (FGF-18) has been shown to regulate the growth plate chondrocyte proliferation, hypertrophy and cartilage vascularization necessary for endochondral ossification. The heparan sulfate proteoglycan perlecan is also critical for growth plate chondrocyte proliferation. FGF-18 null mice exhibit a skeletal dwarfism similar to that of perlecan null mice. Growth plate perlecan contains chondroitin sulfate (CS) and heparan sulfate (HS) chains and FGF-18 is known to bind to heparin and to heparan sulfate from some sources. We used cationic filtration and immunoprecipitation assays to investigate the binding of FGF-18 to perlecan purified from the growth plate and to recombinant perlecan domains expressed in COS-7 cells. FGF-18 bound to perlecan with a K(d) of 145 nM. Near saturation, approximately 103 molecules of FGF-18 bound per molecule of perlecan. At the lower concentrations used, FGF-18 bound with a K(d) of 27.8 nM. This binding was not significantly altered by chondroitinase nor heparitinase digestion of perlecan, but was substantially and significantly reduced by reduction and alkylation of the perlecan core protein. This indicates that the perlecan core protein (and not the CS nor HS chains) is involved in FGF-18 binding. FGF-18 bound equally to full-length perlecan purified from the growth plate and to recombinant domains I-III and III of perlecan. These data indicate that low affinity binding sites for FGF-18 are present in cysteine-rich regions of domain III of perlecan. FGF-18 stimulated 3H-thymidine incorporation in growth plate chondrocyte cultures derived from the lower and upper proliferating zones by 9- and 14-fold, respectively. The addition of perlecan reversed this increased incorporation in the lower proliferating chondrocytes by 74% and in the upper proliferating cells by 37%. These results suggest that perlecan can bind FGF-18 and alter the mitogenic effect of FGF-18 on growth plate chondrocytes.
Assuntos
Condrócitos/citologia , Condrócitos/fisiologia , Fatores de Crescimento de Fibroblastos/administração & dosagem , Fatores de Crescimento de Fibroblastos/metabolismo , Lâmina de Crescimento/metabolismo , Proteoglicanas de Heparan Sulfato/metabolismo , Animais , Sítios de Ligação , Bovinos , Células Cultivadas , Condrócitos/efeitos dos fármacos , Mitógenos/metabolismo , Mitose/efeitos dos fármacos , Mitose/fisiologia , Ligação ProteicaAssuntos
Colágeno Tipo V/fisiologia , Colágeno Tipo XI/fisiologia , Proteínas do Olho/fisiologia , Animais , Artrite/genética , Artrite/metabolismo , Colágeno Tipo V/química , Colágeno Tipo XI/química , Doenças do Tecido Conjuntivo/genética , Doenças do Tecido Conjuntivo/metabolismo , Córnea/química , Córnea/metabolismo , Modelos Animais de Doenças , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/metabolismo , Proteínas do Olho/química , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/metabolismo , Humanos , Camundongos , Descolamento Retiniano/genética , Descolamento Retiniano/metabolismo , Esclera/química , Esclera/metabolismo , Corpo Vítreo/química , Corpo Vítreo/metabolismo , Descolamento do Vítreo/genética , Descolamento do Vítreo/metabolismoRESUMO
During tendon development collagen fibrillogenesis occurs in extracellular micro-domains defined by the tenocytes. This permits cellular regulation of the extracellular steps involved in the tissue-specific matrix assembly required for function. The hypothesis tested here is that collagen V associates with the tenocyte surface where it functions in regulation of collagen assembly and cell-directed fibril deposition. The in vitro and in vivo data demonstrate that collagen V is a quantitatively minor component of the tendon. It is preferentially localized on the tenocyte surface as distinct foci in tendons and in cell culture. In vitro data indicate that this interaction with the tenocyte is not HSPG GAG-dependent. Collagen V is present as the mature, processed form, is absent from the media, and is a significant part of the detergent-insoluble cell layer, presumably as part of a membrane-associated complex. In contrast, procollagen I is not efficiently processed and is found predominantly in the culture media. Our data suggest that the regulatory role of collagen V requires collagen V to occupy a different cellular niche from the structural collagen I. In monolayer cultures, the conversion to the tissue form of collagen V and its deposition with the cell layer suggest efficient engagement of procollagen V with pericellular receptors and processing enzymes. The secretion of collagen I into the media and inefficient processing of procollagen I suggest reduced accessibility to these pericellular molecules due to disengagement from the cell surface. This all points to differential spatial localization of collagen V as a mechanism to optimize its regulatory roles during the cell-surface directed steps in tendon collagen fibril assembly.