Collagen Maturation

Author: Gianpiero Pescarmona
Date: 25/06/2013


Collagens—structure, function, and biosynthesis, 2003

Fibril Formation

Collagen Metabolism Compartimentation

Dioxygenase Reaction Substrates

  • O2
  • 2-oxoglutarate
  • Fe++
  • Ascorbate



Alteration in the extent of collagen I hydroxylation, isolated from femoral heads of women with a femoral neck fracture caused by osteoporosis. 1997

  • The aim of this study was to investigate the extent of lysyl and prolyl hydroxylation of collagen I in osteoporosis and compare it with collagen I from "bone healthy" individuals. Collagen I was isolated from femoral heads of osteoporotic women, from women suffering from osteoarthrosis of the hip, and from healthy women 60-85 years of age. The femoral heads were dissected into compact and trabecular bone of the neck region and from trabecular bone of the head region, and collagen I was extracted by limited pepsin digestion. The amino acid analysis of individual alpha-chains showed a remarkably higher degree of hydroxylation of lysine residues both in the alpha1(I)- and in the alpha2(I)-chains in osteoporotic bone compared with osteoarthrotic and "normal" bone, whereas the prolyl hydroxylation was nearly unchanged. The lysyl overhydroxylation was observed in the compact as well as in the trabecular bone of osteoporotic femoral heads. These biochemical alterations may play a crucial role in the pathogenesis of osteoporosis.

Osteoporosis in longstanding acromegaly: characteristic changes of vertebral trabecular architecture and bone matrix composition. 1991

  • Although it is now 60 years after Erdheim's (1931) detailed description of vertebral alterations in severe acromegaly, it is still unclear whether osteoporosis is a consistent feature of acromegalic bone disease or not. We studied the vertebral trabecular bone of a 44-year-old woman who had suffered active acromegaly for more than 20 years, and compared it with 17 normal as well as 2 osteoporotic controls. Histomorphometry revealed a very low trabecular bone volume and thus documented the presence of osteoporosis. The mean trabecular plate thickness was strikingly increased in acromegaly (possibly caused in part by a low-dose fluoride treatment), whereas it was normal or reduced in the osteoporotic controls. The meticulous analysis showed islands of cartilaginous tissue in the core of the acromegalic trabeculae which were not present in any other sample. In these areas collagen II was detected by immunohistochemistry. Biochemical analysis revealed that collagen II accounted for 7% of the total collagenous matrix. The degree of hydroxylation of lysyl residues of collagen I was close to the average value of all control samples studied. Our data show that osteoporosis can occur in acromegaly and that it is characterized by unusual architectural and compositional features. These findings challenge the prevailing view that the matrix of osteoporotic bone always shows a normal composition.

Overhydroxylation of lysyl residues is the initial step for altered collagen cross-links and fibril architecture in fibrotic skin. 1999

^ The results provide convincing evidence that morphometric changes associated with osteopenia in adult bone are accompanied by an altered level of lysyl hydroxylation of the alpha 2(I)-chain of collagen I.

Regional alterations of type I collagen in rat tibia induced by skeletal unloading.2002

  • The collagen cross-linking and the extent of lysine (Lys) hydroxylation in unloaded bones were significantly altered in proximal epiphysis, diaphysis, and, in particular, proximal metaphysis but not in distal regions.
    Matched in Chemicals: Collagen Type I.

The role of small leucine-rich proteoglycans in collagen fibrillogenesis

Sebastian Kalamajski, , 2010

  • Small leucine-rich proteoglycans/proteins (SLRPs) are associated with collagen fibril formation, and therefore important for the proper formation of extracellular matrices. SLRPs are differentially expressed in tissues and during pathological conditions, contributing to the development of connective tissue properties. The binding of SLRPs to collagens have recently been characterized, and may give some clues to the significance of these interactions. In this mini review, we summarize published work in this field, and propose several mechanisms for how SLRPs can control collagen matrix structure and function. SLRPs appear to influence collagen cross-linking patterns. We also propose that the SLRP-collagen interactions can assist in the process of juxtaposing the collagen monomers by steric hindrance or by directly connecting two collagen monomers during the fibril growth.

2013-06-26T09:26:06 - Gianpiero Pescarmona

Potential regulatory steps of the collagen biosynthesis pathway.

  1. Epigenetic level: HDAC inhibitors.
  2. Post-transcriptional level: mRNA translation is reduced by miRNAs/siRNAs.
  3. Post-translational level: prolyl-4-hydroxylase inhibitors reduce the stability of the procollagen triple helix.
  4. Reduction/inhibition of the collagen chaperone hsp47 (pink crescent symbol) also reduces stability of the procollagen triple helices, resulting in intracellular retention and degradation.
  5. Post-secretional level: Inhibition of procollagen proteinases (scissors symbol) prevents deposition of insoluble collagen molecules on the cell layer.
  6. Collagen crosslinking: Inhibition of lysyl oxidase (LOX) hypothetically renders the collagen more susceptible to degradation.
  7. An increase of MMP1 (orange Pacman symbol) results in faster collagen degradation and turnover.

Focus on collagen: in vitro systems to study fibrogenesis and antifibrosis _ state of the art, 2009

HIF1α is a central regulator of collagen hydroxylation and secretion under hypoxia during bone development, 2012

  • HIF1α regulates collagen hydroxylation and secretion in the hypoxic growth plate. A model that summarizes our findings on the role of HIF1α in regulating collagen hydroxylation and secretion. Left panel, wild-type chondrocyte; right panel, Hif1a-deficient chondrocyte. (I, left) In the hypoxic growth plate, HIF1α directly activates the transcription of P4ha1, P4ha2 and P4hb, the subunits of collagen prolyl 4-hydroxylase enzyme (P4H, marked in orange). In addition, HIF1α directly activates the transcription of pyruvate dehydrogenase kinase 1 (Pdk1). (II, left) PDK1 inhibits oxygen consumption through inhibition of the TCA cycle to maintain oxygen homeostasis. (III, left) Oxygen is used by P4H to hydroxylate collagen. Collagen hydroxylation is required for the formation of the triple helix (procollagen). (IV, left) Normal collagen secretion. (I, right) The expression of P4ha1, P4ha2, P4hb and Pdk1 is reduced in Hif1a-deficient chondrocyte. (II, right) Oxygen levels are reduced as a result of reduced Pdk1 expression and increased oxygen consumption by the TCA cycle. (III, right) Collagen hydroxylation and folding is impaired due to reduced P4H levels and reduced oxygen levels. Unfolded collagen accumulates in the ER. (IV, right) The accumulation of unfolded collagen induces ER stress and results in impaired collagen secretion in Hif1a-deficient chondrocyte.

HIF and PH4

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