Absence ofFKBP10in recessive type XI osteogenesis imperfecta leads to diminished collagen cross-linking and reduced collagen deposition in extracellular matrix

Abstract

Recessive osteogenesis imperfecta (OI) is caused by defects in genes whose products interact with type I collagen for modification and/or folding. We identified a Palestinian pedigree with moderate and lethal forms of recessive OI caused by mutations in FKBP10 or PPIB, which encode endoplasmic reticulum resident chaperone/isomerases FKBP65 and CyPB, respectively. In one pedigree branch, both parents carry a deletion in PPIB (c.563_566delACAG), causing lethal type IX OI in their two children. In another branch, a child with moderate type XI OI has a homozygous FKBP10 mutation (c.1271_1272delCCinsA). Proband FKBP10 transcripts are 4% of control and FKBP65 protein is absent from proband cells. Proband collagen electrophoresis reveals slight band broadening, compatible with ≈10% overmodification. Normal chain incorporation, helix folding, and collagen Tm support a minimal general collagen chaperone role for FKBP65. However, there is a dramatic decrease in collagen deposited in culture despite normal collagen secretion. Mass spectrometry reveals absence of hydroxylation of the collagen telopeptide lysine involved in cross-linking, suggesting that FKBP65 is required for lysyl hydroxylase activity or access to type I collagen telopeptide lysines, perhaps through its function as a peptidylprolyl isomerase. Proband collagen to organics ratio in matrix is approximately 30% of normal in Raman spectra. Immunofluorescence shows sparse, disorganized collagen fibrils in proband matrix.

FK506-Binding Protein 10, a Potential Novel Drug Target for Idiopathic Pulmonary Fibrosis

“…Figure 6C and 6D) as well as in decreased secreted collagen (Figure 8). In line with our results, deficiency of FKBP10 in osteogenesis imperfecta has been shown to attenuate collagen secretion and, moreover, decrease the extent of lysyl hydroxylation and extracellular collagen cross-linking and increase protease sensitivity of extracellular collagen I in dermal fibroblasts from patients with osteogenesis imperfecta (15,17,18). Surprisingly, loss of FKBP10 affected collagen levels not only on protein but also on transcript levels ( Figure 7A).…”

“…Surprisingly, loss of FKBP10 affected collagen levels not only on protein but also on transcript levels ( Figure 7A). This is unexpected, as FKBP10-as a chaperone and peptidyl-prolyl isomerase-is mainly ascribed a post-transcriptional role in procollagen I processing (11,14,15,17,18). Interestingly, loss of FKBP10 also attenuated the expression of the TGF-b-responsive genes PAI1 and a-SMA (Figures 6D and 7A).…”

“…Although FKBP10 has been suggested to be important for normal lung development, with little expression in normal adult tissues, its expression appears to be reactivated during lung fibrosis (26,27). Considering the impact of FKBP10 on collagen cross-linking (15,17,18) and the effects described herein on collagen secretion, FKBP10 might provide a very specific and effective drug target for treatment of IPF. n total secreted collagen (% of ctrl) Figure 9.…”

“…Collagen triple helix formation heavily relies on proline isomerization to trans-proline as a prerequisite of linear chain assembly (14). Mutations in FKBP10 lead to collagen-related disorders such as osteogenesis imperfecta, and studies in the last 4 years have suggested an association of these mutations with attenuated collagen secretion and diminished collagen I cross-linking in dermal fibroblasts and bone (15)(16)(17)(18). A recent study showed that Fkbp10 2/2 mouse embryos are postnatally lethal and display reduced collagen cross-linking in calvarial bone (19).…”

Collagen Type I as a Ligand for Receptor-Mediated Signaling

“…In a homozygous patient with HSP47 missense mutation, it was demonstrated that HSP47, potentially acting in cooperation with immunophilin FKBP65, encoded by FKBP10, is important for proper trafficking of type I procollagen to the Golgi [57]. Mutations in FKBP10 also cause moderately severe osteogenesis imperfecta [58,59] with decreased collagen cross-linking, resulting in sparsity and disorder of collagen fibril deposition [60].…”