Bone and Soft Tissue Turnover in Relation to All-cause Mortality in Postmenopausal Women.

BACKGROUND: The relationship between levels of extracellular matrix (ECM) turnover and mortality is currently unknown. The study aimed to determine if levels of ECM turnover are predictors of all-cause mortality in a large cohort of postmenopausal women. METHODS: 5,855 postmenopausal Danish women enrolled in the Prospective Epidemiologic Risk Factor (PERF) study. Baseline demographics and serum were collected at registration. Dates of death were obtained from the Danish Death Registry. ECM turnover was evaluated by serological biomarkers measuring bone (telopeptide of type I collagen [CTX-1] and osteocalcin) and soft tissue (formation of type VI collagen [PRO-C6], MMP-degraded type IV collagen [C4M], formation of type III collagen [PRO-C3], and MMP-degraded type I collagen [C1M]) turnover. Multivariate Cox analyses were performed with 3, 5, and 15 years of follow-up. RESULTS: The association of bone turnover (CTX-1 and osteocalcin) with all-cause mortality was U-shaped for all time periods. After adjustment for possible confounders, the lowest quintile of bone formation and degradation remained significant for all time periods. We observed J-shaped association between all-cause mortality and PRO-C6, C4M, and PRO-C3, and there was a linear association between C1M and all-cause mortality. After adjustment for possible confounders, the highest quintile of the soft tissue turnover biomarkers (PRO-C6, C4M, PRO-C3, and C1M) remained significantly associated with all-cause mortality for all time periods. CONCLUSION: Both low and high levels of tissue turnover were associated with increased risk of all-cause mortality in postmenopausal women. Overall, these results highlight the importance of bone and soft tissue homeostasis.

[A modern viewpoint on structure and evolution of collagens. I. Fibrillar collagens].

This review summarizes current data on structure of the most representative group of the collagen family--fibrillar collagens. Attention has been focused on structural organization of individual domains and their functional role in the hierarchical stacking of alpha-chains of collagens. There is presented characteristics of the main stages of biosynthesis and of supramolecular processing of fibrillar collagens. Also considered are some aspects of evolution of fibrillar collagens. The role of duplication of genome and genes, intergene rearrangements, and exon shuffling in evolution of collagen genes is discussed.

Comparative study of clinicofunctional staging of oral submucous fibrosis with qualitative analysis of collagen fibers under polarizing microscopy.

OBJECTIVE: The aim of the study was to assess the severity of the disease in oral submucous fibrosis (OSF), correlate the clinical, functional staging with histopathological staging, and analyze collagen distribution in different stages of OSF using the picrosirius red stain under polarizing microscopy. MATERIALS AND METHODS: The study included randomly incorporated 50 subjects, of whom 40 were patients with OSF, and 10 were in the control group. Clinical, functional staging in OSF cases was done depending upon definite criteria. A histopathological study was conducted using the hematoxylin and eosin stain and picrosirius red stain. Collagen fibers were analyzed for thickness and polarizing colors. Furthermore, clinical, functional, and histopathological stages were compared. STATISTICAL ANALYSIS: Descriptive data which included mean, SD, and percentages were calculated for each group. Categorical data were analyzed by the chi-square test. Multiple group comparisons were made by one-way ANOVA followed by Student's t-test for pairwise comparisons. For all tests, a P-value of 0.05 or less was considered for statistical significance. RESULTS: As the severity of the disease increased, clinically, there was definite progression in subjective and objective symptoms. Polarized microscopic, examination revealed, there was a gradual decrease in the green-greenish yellow color of the fibers and a shift to orange red-red color with increase in severity of the disease. Thereby, it appeared that the tight packing of collagen fibers in OSF progressively increased as the disease progressed from early to advanced stages. We observed that the comparison of functional staging with histopathological staging was a more reliable indicator of the severity of the disease. CONCLUSION: In the present study, we observed that mouth opening was restricted with advancing stages of OSF. The investigation also points to the importance of assessing the cases of OSF, especially with regard to functional and histological staging in planning the treatment.

Collagen types I, III, and V constitute the thick collagen fibrils of the mouse decidua.

A mammal's endometrium is deeply remodeled while receiving and implanting an embryo. In addition to cell proliferation and growth, endometrial remodeling also comprises synthesis and degradation of several molecular components of the extracellular matrix. All of these events are orchestrated by a precise sequence of ovarian hormones and influenced by several types of cytokines. As we have previously reported, an intriguing and rapid increase in collagen fibril diameter occurs in the decidualized areas of the endometrium, surrounding the implantation crypt, whereas collagen fibrils situated far from the embryo remain unchanged. Collagen fibrilogenesis is a complex molecular process coordinated by a number of factors, such as the types and amounts of glycosaminoglycans and proteoglycans associated with collagen molecules. Collagen genetic type, mechanical stress, aging, and other factors not yet identified also contribute to this development. A recent study suggests that thick fibrils from mouse decidua are formed, at least in part, by aggregation of thin fibrils existing in the stroma before the onset of decidualization. In the present ultrastructural study using single and double immunogold localization, we showed that both thin and thick collagen fibrils present in the mouse pregnant endometrium endometrium are heterotypic structures formed at least by type I, type III, and type V collagens. However, type V collagen predominates in the thick collagen fibrils, whereas it is almost absent of the thin collagen fibrils. The putative role of type V homotrimer in the rapid increase of the diameter of collagen fibrils of the mouse decidua is discussed.

Invertebrate data predict an early emergence of vertebrate fibrillar collagen clades and an anti-incest model.

Fibrillar collagens are involved in the formation of striated fibrils and are present from the first multicellular animals, sponges, to humans. Recently, a new evolutionary model for fibrillar collagens has been suggested (Boot-Handford, R. P., Tuckwell, D. S., Plumb, D. A., Farrington Rock, C., and Poulsom, R. (2003) J. Biol. Chem. 278, 31067-31077). In this model, a rare genomic event leads to the formation of the founder vertebrate fibrillar collagen gene prior to the early vertebrate genome duplications and the radiation of the vertebrate fibrillar collagen clades (A, B, and C). Here, we present the modular structure of the fibrillar collagen chains present in different invertebrates from the protostome Anopheles gambiae to the chordate Ciona intestinalis. From their modular structure and the use of a triple helix instead of C-propeptide sequences in phylogenetic analyses, we were able to show that the divergence of A and B clades arose early during evolution because alpha chains related to these clades are present in protostomes. Moreover, the event leading to the divergence of B and C clades from a founder gene arose before the appearance of vertebrates; altogether these data contradict the Boot-Handford model. Moreover, they indicate that all the key steps required for the formation of fibrils of variable structure and functionality arose step by step during invertebrate evolution.

The interaction between Sillence type and BMD in osteogenesis imperfecta.

Clinical studies with bisphosphonates in children with osteogenesis imperfecta (OI) show an increase in BMD and a decrease in fracture rate. Bone strength in children with OI is not only influenced by changes in BMD but also by changes in collagen I structure of the organic bone matrix. Therefore, we studied the interaction between these two factors in a cross-sectional, single center study including 54 children. We assumed that vertebral deformities in OI represent an unbalance between load and bone strength. Body weight was considered to be a well quantifiable load on vertebral bodies. BMD served as a marker, representing the amount of bone tissue available for vertebral load bearing, and the Sillence classification, either type I or III/IV, as a marker representing the quality of the organic bone matrix. Independent associations were observed between the prevalence of vertebral deformities and (1) Sillence type (OR: 5.7, 95%Cl:1.2-26.8), (2) BMD (OR: 0.003, 95%Cl: 0-0.25) and (3) body weight (OR: 1.15, 95%Cl: 1.05-1.25). Regarding the anthropometrical differences among the different types of OI, the BMD/body weight ratio was introduced to evaluate the BMD in relation to body size. Prevalent vertebral deformities were associated with low BMD/body weight ratios (OR: 0.04, 95%Cl: 0.008-0.2) in OI type I, but no association was found in type III/IV. It was concluded that BMD and Sillence type have independent relationships with vertebral deformities. The BMD/body weight ratio correlates with vertebral deformities in children with OI type I. Its meaning in types III/IV needs further research with larger samples because of the relatively high prevalence of vertebral deformities in this group.

The ultrastructure of periductal connective tissue and distinctive populations of collagen fibrils associated with ductal epithelia of exocrine glands.

The ultrastructure of the connective tissue around the intraglandular ducts was observed in rat exocrine glands. Connective tissue with a dense population of collagen fibrils was found either around the ducts and blood vessels (perivasculoductal connective tissue; PVDCT) as in the lacrimal and salivary glands and liver, or solely surrounding the ducts (periductal connective tissue; PDCT) as in the exocrine pancreas, whereas the interlobular and intralobular interstitium of the glands-except for the liver-contained substantially fluid-filled spaces without collagen fibrils. The PVDCT and PDCT of these glands contained two populations of collagen fibrils-fibroblast-associated and epithelium-associated-although the development and density of these fibrils varied considerably in individual glands. Both populations of collagen fibrils were most developed in the lacrimal glands, in which the basal aspects of the ductal epithelium and the basement membrane showed considerable undulation associated with a distinctive peribasement membrane zone with amorphous matter and a small population of the fibrils. In the parotid and submandibular glands, both populations were distinct, though poorly developed. In the exocrine pancreas and hepatic Glisson's sheath, the two populations of collagen fibrils were moderately developed, and the basal aspects of the ductal epithelium were characterized by prominent invaginations in which the multilaminar basement membranes and the epithelium-associated collagen fibrils were frequently engulfed. These observations provide evidence that the two populations of collagen fibrils around the ducts are found universally in exocrine glands, and support the hypothesis of the collagen fibril-synthesizing and -secreting ability of ductal epithelial cells.

Collagen of articular cartilage.

The extracellular framework and two-thirds of the dry mass of adult articular cartilage are polymeric collagen. Type II collagen is the principal molecular component in mammals, but collagens III, VI, IX, X, XI, XII and XIV all contribute to the mature matrix. In developing cartilage, the core fibrillar network is a cross-linked copolymer of collagens II, IX and XI. The functions of collagens IX and XI in this heteropolymer are not yet fully defined but, evidently, they are critically important since mutations in COLIX and COLXI genes result in chondrodysplasia phenotypes that feature precocious osteoarthritis. Collagens XII and XIV are thought also to be bound to fibril surfaces but not covalently attached. Collagen VI polymerizes into its own type of filamentous network that has multiple adhesion domains for cells and other matrix components. Collagen X is normally restricted to the thin layer of calcified cartilage that interfaces articular cartilage with bone.