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Bone morphogenetic proteins: multifunctional regulators of vertebrate development.

Collagen is most abundant in animal tissues as very long fibrils with a characteristic axial periodic structure. The fibrils provide the major biomechanical scaffold for cell attachment and anchorage of macromolecules, allowing the shape and form of tissues to be defined and maintained. How the fibrils are formed from their monomeric precursors is the primary concern of this review. Collagen fibril formation is basically a self-assembly process (i.e. one which is to a large extent determined by the intrinsic properties of the collagen molecules themselves) but it is also sensitive to cell-mediated regulation, particularly in young or healing tissues. Recent attention has been focused on "early fibrils' or "fibril segments' of approximately 10 microns in length which appear to be intermediates in the formation of mature fibrils that can grow to be hundreds of micrometers in length. Data from several laboratories indicate that these early fibrils can be unipolar (with all molecules pointing in the same direction) or bipolar (in which the orientation of collagen molecules reverses at a single location along the fibril). The occurrence of such early fibrils has major implications for tissue morphogenesis and repair. In this article we review the current understanding of the origin of unipolar and bipolar fibrils, and how mature fibrils are assembled from early fibrils. We include preliminary evidence from invertebrates which suggests that the principles for bipolar fibril assembly were established at least 500 million years ago.

/pdf/collagen-fibril-formation-39ffs3sfgq.pdf

Collagen fibril formation

The extracellular matrix (ECM), and especially the connective tissue with its collagen, links tissues of the body together and plays an important role in the force transmission and tissue structure maintenance especially in tendons, ligaments, bone, and muscle. The ECM turnover is influenced by physical activity, and both collagen synthesis and degrading metalloprotease enzymes increase with mechanical loading. Both transcription and posttranslational modifications, as well as local and systemic release of growth factors, are enhanced following exercise. For tendons, metabolic activity, circulatory responses, and collagen turnover are demonstrated to be more pronounced in humans than hitherto thought. Conversely, inactivity markedly decreases collagen turnover in both tendon and muscle. Chronic loading in the form of physical training leads both to increased collagen turnover as well as, dependent on the type of collagen in question, some degree of net collagen synthesis. These changes will modify the mechanical properties and the viscoelastic characteristics of the tissue, decrease its stress, and likely make it more load resistant. Cross-linking in connective tissue involves an intimate, enzymatical interplay between collagen synthesis and ECM proteoglycan components during growth and maturation and influences the collagen-derived functional properties of the tissue. With aging, glycation contributes to additional cross-linking which modifies tissue stiffness. Physiological signaling pathways from mechanical loading to changes in ECM most likely involve feedback signaling that results in rapid alterations in the mechanical properties of the ECM. In developing skeletal muscle, an important interplay between muscle cells and the ECM is present, and some evidence from adult human muscle suggests common signaling pathways to stimulate contractile and ECM components. Unaccostumed overloading responses suggest an important role of ECM in the adaptation of myofibrillar structures in adult muscle. Development of overuse injury in tendons involve morphological and biochemical changes including altered collagen typing and fibril size, hypervascularization zones, accumulation of nociceptive substances, and impaired collagen degradation activity. Counteracting these phenomena requires adjusted loading rather than absence of loading in the form of immobilization. Full understanding of these physiological processes will provide the physiological basis for understanding of tissue overloading and injury seen in both tendons and muscle with repetitive work and leisure time physical activity.

Role of Extracellular Matrix in Adaptation of Tendon and Skeletal Muscle to Mechanical Loading

Metastasis is the cause of death for patients with many types of cancer, but the process of tumour cell dissemination is poorly understood. As primary tumours are three-dimensional, departure of cells from primary tumours has been difficult to study. Multiphoton microscopy has been developed for in vivo imaging and, using this technique, we are beginning to understand how invasive tumour cells move.

Intravital imaging of cell movement in tumours

Bone morphogenetic proteins in development

Bone morphogenetic proteins (BMPs) are bone-derived factors capable of inducing ectopic bone formation. Unlike other BMPs, BMP-1 is not like transforming growth factor-β (TGF-β), but it is the prototype of a family of putative proteases implicated in pattern formation during development in diverse organisms. Although some members of this group, such as Drosophila tolloid (TLD), are postulated to activate TGF-β-like proteins, actual substrates are unknown. Procollagen C-proteinase (PCP) cleaves the COOH-propeptides of procollagens I, II, and III to yield the major fibrous components of vertebrate extracellular matrix. Here it is shown that BMP-1 and PCP are identical. This demonstration of enzymatic activity for a BMP-1/TLD-like protein links an enzyme involved in matrix deposition to genes involved in pattern formation.

http://science.sciencemag.org/content/sci/271/5247/360.full.pdf

Luba Biniaminov

Papers

Bone Morphogenetic Protein-1: The Type I Procollagen C-Proteinase