Collagens V and XI comprise a single regulatory type of fibrilforming 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؊/؊ ) 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.Abnormal collagen fibril formation is characteristic of the classic form of Ehlers-Danlos syndrome (EDS).2 Patients with classic EDS (types I and II) have a broad spectrum of generalized connective tissue defects including hyper-extensible skin, fragile skin with wide, depressed, callused scarring, inguinal hernias, and rectal prolapse as well as aortic root dilation and valve prolapse (1, 2). In addition, laxity in the joints, leading to instability and easy dislocation as well as joint hyper-extensibility, is a characteristic feature resulting from dysfunctional tendons and ligaments. More than half of all instances of classic EDS have been linked to heterozygous mutations in the genes for collagen V (3-13). The most common mutation type in classic EDS is one that results in a functional loss of one Col5a1 allele (14, 15).Collagen V is a fibril-forming collagen. The fibril-forming collagen subfamily includes collagens I, II, III, V, XI, XXIV, and XXVII, and the genes cluster into three distinct clades (16). Collagens I, II, and III are the major components of all collagen fibrils. Collagens V and XI are quantitatively minor collagens found as heterotypic fibrils with collagens I, II, and III and have a regulatory function in fibrillogenesis (17). Collagens XXIV and XXVII have structural differences relative to collagens I, II III, V, and XI, and their specific roles remain to be elucida...

Purpose of Review Osteogenesis imperfecta (OI), 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 OI as a collagen-related disorder, where autosomal dominant type I collagen defects cause most cases, 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 OI. Recent Findings BRIL and PEDF defects cause types V and VI OI via defective bone mineralization, while defects in CRTAP, P3H1 and CyPB cause types VII-IX via defective collagen post-translational modification. Hsp47 and FKBP65 defects cause types X and XI OI via aberrant collagen crosslinking, folding and chaperoning, while defects in SP7, WNT1, TRIC-B and OASIS disrupt osteoblast development. Finally, absence of the type I collagen C-propeptidase BMP1 causes type XII OI 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 OI types by shared mechanism to simplify current nosology, and should prod investigations into common pathways in OI. Such investigations could yield critical information on cellular and bone tissue mechanisms and translate to new mechanistic insight into clinical therapies for patients.

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StructureThe collagens are a family of 28 extracellular matrix glycoproteins. Collagens are composed of 3 polypeptides, called alpha chains. Each α chain contains at least one stiff, rod-like domain of varying length with a glycine at every third residue that can form a triple helix, i.e., collagenous domain. Collagens V and XI are members of the fibril-forming class of collagens, along with collagens I, II, III, XXIV and XXVII. Collagens V and XI comprise a subclass of regulatory fibrillar collagens that co-assemble with collagens I, II and III. All collagens are trimers composed of 3 α chains with at least one triple helical or collagen (COL) domain. Alpha chains of collagens V (P20908 and P25940) and XI (P12107 and P13942) are encoded by genes with different phylogenetic origins, belonging to different clades or `ancestral groups' (clade 2) from collagens I, II and III (clade 1) or XXIV and XXVII (clade 3). Clade 1 also contains the α2(V) gene (P05997; i.e., the α2 chain of collagen V) and the α1(II) gene, termed α3(XI) when part of a collagen XI trimer (P02458). These genes code for multi-domain polypeptide chains with features common to all fibrillar collagens: a signal peptide; an N-terminal non-collagenous region (NC3); a short N-terminal triple helical domain of interrupted Gly-X-Y repeats (COL2), where X and Y can be any amino acid, but are often proline and hydroxyproline, respectively; a short non-collagenous domain (NC2 or `hinge'); the main triple helical or collagenous domain of continuous (Gly-X-Y) n repeats (COL1); and a non-collagenous C-propeptide (NC1) (Fig.1).The V/XI α chains are assembled as procollagens with terminal N-and C-propeptides that are cleaved by specific enzymes to produce the mature collagen molecule. The first half of the human α1(V) N-propeptide has 73% homology with the human α1(XI) chain; there is 83% homology between the COL1 domains and ~76% between the C-propeptides. These Nand C-propeptides differ from those of the other fibrillar collagens. It is based on these properties that collagens V and XI are grouped as a separate subclass. The C-propeptides are removed by cleavage of the NC1 domain. The N-propeptide is composed of the NC3, COL2 and NC2 domains. The NC3 domain of all V/XI α chains, except α2(V) and α3(XI), have a PARP (proline-and arginine-rich protein) domain and a variable (VAR) domain. Chainspecific differences in the N-propeptide result in differences in N-propeptide processing.