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IFT20 is critical for collagen biosynthesis in craniofacial bone formation.

ABSTRACT: Intraflagellar transport (IFT) is essential for assembling primary cilia required for bone formation. Disruption of IFT frequently leads to bone defects in humans. While it has been well studied about the function of IFT in osteogenic cell proliferation and differentiation, little is known about its role in collagen biosynthesis during bone formation. Here we show that IFT20, the smallest IFT protein in the IFT-B complex, is important for collagen biosynthesis in mice. Deletion of Ift20 in craniofacial osteoblasts displayed bone defects in the face. While collagen protein levels are unaffected by loss of Ift20, collagen cross-linking was significantly altered. In both Ift20:Wnt1-Cre and Ift20:Ocn-Cre mice the bones exhibit increased hydroxylysine-aldehyde deived cross-linking, and decreased lysine-aldehyde derived cross-linking. To obtain insight into the molecular mechanisms, we examined the expression levels of telopeptidyl lysyl hydroxylase 2 (LH2), and associated chaperone complexes. The results demonstrated that, while LH2 levels were unaffected by loss of Ift20, its chaperone, FKBP65, was significantly increased in Ift20:Wnt1-Cre and Ift20:Ocn-Cre mouse calvaria as well as femurs. These results suggest that IFT20 plays a pivotal role in collagen biosynthesis by regulating, in part, telopeptidyl lysine hydroxylation and cross-linking in bone. To the best of our knowledge, this is the first to demonstrate that the IFT components control collagen post-translational modifications. This provides a novel insight into the craniofacial bone defects associated with craniofacial skeletal ciliopathies.

SUBMITTER: Yamaguchi H

PROVIDER: S-EPMC7744399 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Implant osteoinduction and subsequent osteogenic activity are critical events that need improvement for regenerative healing of large craniofacial bone defects. Here we describe the augmentation of the mineral content of a class of mineralized collagen scaffolds under development for craniomaxillofacial bone regeneration via the inclusion of zinc ions to promote osteogenesis in vitro. Zinc is an essential trace element in skeletal tissue and bone, with soluble zinc being shown to promote osteogenic differentiation of porcine adipose derived stem cells. We report the development of a new class of zinc functionalized scaffolds fabricated by adding zinc sulfate to a mineralized collagen-glycosaminoglycan precursor suspension that was then freeze dried to form a porous biomaterial. We report analysis of zinc functionalized scaffolds via imaging (scanning electron microscopy), mechanical testing (compression), and compositional (X-ray diffraction, inductively coupled plasma mass spectrometry) analyses. Notably, zinc-functionalized scaffolds display morphological changes to the mineral phase and altered elastic modulus without substantially altering the composition of the brushite phase or removing the micro-scale pore morphology of the scaffold. These scaffolds also display zinc release kinetics on the order of days to weeks and promote successful growth and pro-osteogenic capacity of porcine adipose derived stem cells cultured within these zinc scaffolds. Taken together, we believe that zinc functionalized scaffolds provide a unique platform to explore strategies to improve in vivo osteogenesis in craniomaxillofacial bone injuries models. STATEMENT OF SIGNIFICANCE: Craniomaxillofacial bone defects that arise from traumatic, congenital, and post-oncologic origins cannot heal on their own and often require surgical intervention. We have developed a class of mineralized collagen scaffolds that promotes osteogenesis and bone regeneration. Here we describe the inclusion of zinc sulfate into the mineralized collagen scaffold to improve osteogenesis. Zinc functionalized scaffolds demonstrate altered crystallite microstructure but consistent Brushite chemistry, improved mechanics, and promote zinc transporter expression while supporting stem cell viability, osteogenic differentiation, and mineral biosynthesis.

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IFT20 is critical for collagen biosynthesis in craniofacial bone formation.

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