Collagen is the most abundant protein in animals. This fibrous, structural protein comprises a right-handed bundle of three parallel, left-handed polyproline II-type helices. Much progress has been made in elucidating the structure of collagen triple helices and the physicochemical basis for their stability. New evidence demonstrates that stereoelectronic effects and preorganization play a key role in that stability. The fibrillar structure of type I collagen—the prototypical collagen fibril—has been revealed in detail. Artificial collagen fibrils that display some properties of natural collagen fibrils are now accessible using chemical synthesis and self-assembly. A rapidly emerging understanding of the mechanical and structural properties of native collagen fibrils will guide further development of artificial collagenous materials for biomedicine and nanotechnology.

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Collagen Structure and Stability

Collagens are the most abundant proteins in mammals. The collagen family comprises 28 members that contain at least one triple-helical domain. Collagens are deposited in the extracellular matrix where most of them form supramolecular assemblies. Four collagens are type II membrane proteins that also exist in a soluble form released from the cell surface by shedding. Collagens play structural roles and contribute to mechanical properties, organization, and shape of tissues. They interact with cells via several receptor families and regulate their proliferation, migration, and differentiation. Some collagens have a restricted tissue distribution and hence specific biological functions.

The Collagen Family

Collagen fibrillogenesis: fibronectin, integrins, and minor collagens as organizers and nucleators.

A new paradigm has emerged for osteogenesis imperfecta as a collagen-related disorder. The more prevalent autosomal dominant forms of osteogenesis imperfecta are caused by primary defects in type I collagen, whereas autosomal recessive forms are caused by deficiency of proteins which interact with type I procollagen for post-translational modification and/or folding. Factors that contribute to the mechanism of dominant osteogenesis imperfecta include intracellular stress, disruption of interactions between collagen and noncollagenous proteins, compromised matrix structure, abnormal cell-cell and cell-matrix interactions and tissue mineralization. Recessive osteogenesis imperfecta is caused by deficiency of any of the three components of the collagen prolyl 3-hydroxylation complex. Absence of 3-hydroxylation is associated with increased modification of the collagen helix, consistent with delayed collagen folding. Other causes of recessive osteogenesis imperfecta include deficiency of the collagen chaperones FKBP10 or Serpin H1. Murine models are crucial to uncovering the common pathways in dominant and recessive osteogenesis imperfecta bone dysplasia. Clinical management of osteogenesis imperfecta is multidisciplinary, encompassing substantial progress in physical rehabilitation and surgical procedures, management of hearing, dental and pulmonary abnormalities, as well as drugs, such as bisphosphonates and recombinant human growth hormone. Novel treatments using cell therapy or new drug regimens hold promise for the future.

New perspectives on osteogenesis imperfecta.

Hypophosphatemia is a genetically heterogeneous disease. Here, we mapped an autosomal recessive form (designated ARHP) to chromosome 4q21 and identified homozygous mutations in DMP1 (dentin matrix protein 1), which encodes a non-collagenous bone matrix protein expressed in osteoblasts and osteocytes. Intact plasma levels of the phosphaturic protein FGF23 were clearly elevated in two of four affected individuals, providing a possible explanation for the phosphaturia and inappropriately normal 1,25(OH)2D levels and suggesting that DMP1 may regulate FGF23 expression.

DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis

Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta

Location of 3-hydroxyproline residues in collagen types I, II, III, and V/XI implies a role in fibril supramolecular assembly.

Collagen XI chain misassembly in cartilage of the chondrodysplasia (cho) mouse.

Nat. Genet. 39, 359–365 (2007); published online 4 February 2007; corrected after print 26 June 2008 In the version of this article initially published, the nucleotide positions of the mutations in the LEPRE1 cDNA and genomic DNA sequence in Table 1, Supplementary Table 1 and Supplementary Figure 1 were incorrectly numbered relative to the first nucleotide of exon 1 rather than the first nucleotide of the LEPRE1 start codon.

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Melissa A Scott

Papers

Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta

Location of 3-hydroxyproline residues in collagen types I, II, III, and V/XI implies a role in fibril supramolecular assembly.

Collagen XI chain misassembly in cartilage of the chondrodysplasia (cho) mouse.

Correction: Corrigendum: Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta