Publication
Dittmann, K., Wuelling, M., Uhmann, A., Dullin, C., Hahn, H., Schweyer, S., Vortkamp, A., Wienands, J. (2014). Inactivation of Patched 1 in chondrocytes causes spinal fusion without inflammation. Arthritis Rheum 66(4):831-40.
Abstract
Objective. During development of the vertebrate skeleton chondrocytes form a cartilage template that is gradually replaced by bone. Hormones of the Hedgehog (Hh) family have been implicated in the ossification process but their exact role to normal or pathogenic bone formation is unclear. The aims of this study were first, the establishment of a genetic tool that allows the discrete inactivation of genes in spinal chondrocytes, and second, the in vivo investigation of how chondrocyte-specific ablation of the inhibitory Hh receptor Patched1 (Ptch1) affects skeleton integrity. Methods. A Cre-deleter mouse strain for gene recombination in spinal chondrocytes was identified by in situ hybridization and histology (mb1-Cre). Breeding of mb1-Cre+/- animals with mice that harbor a loxP-flanked Ptch1 gene (Ptch1flox/flox ) abrogated the inhibition of the Hh signaling pathway in chondrocytes. The skeleton integrity of F1-mice was characterized by high-resolution flat panel-based volume-computed tomography (fpVCT) and histological staining procedures. Results. During the first weeks after birth all mb1-Cre+/- /Ptch1flox/flox mice developed a progressive spinal fusion with malformation of the vertebrae. The aclampsia phenotype was caused by aberrant chondrocyte proliferation in the intervertebral discs that blocked endochondral ossification. Importantly, the disease pattern occurred in an inflammation-independent manner. Conclusion. Chronic activation of the Hh signal pathway in spinal chondrocytes can trigger an ankylosing spine morphology without immune cell contributions. Hence, the destruction of cartilage and loss of axial joint integrity can result from chondrocyte-intrinsic defects of monogenic origin. © 2013 American College of Rheumatology.
Objective. During development of the vertebrate skeleton chondrocytes form a cartilage template that is gradually replaced by bone. Hormones of the Hedgehog (Hh) family have been implicated in the ossification process but their exact role to normal or pathogenic bone formation is unclear. The aims of this study were first, the establishment of a genetic tool that allows the discrete inactivation of genes in spinal chondrocytes, and second, the in vivo investigation of how chondrocyte-specific ablation of the inhibitory Hh receptor Patched1 (Ptch1) affects skeleton integrity. Methods. A Cre-deleter mouse strain for gene recombination in spinal chondrocytes was identified by in situ hybridization and histology (mb1-Cre). Breeding of mb1-Cre+/- animals with mice that harbor a loxP-flanked Ptch1 gene (Ptch1flox/flox ) abrogated the inhibition of the Hh signaling pathway in chondrocytes. The skeleton integrity of F1-mice was characterized by high-resolution flat panel-based volume-computed tomography (fpVCT) and histological staining procedures. Results. During the first weeks after birth all mb1-Cre+/- /Ptch1flox/flox mice developed a progressive spinal fusion with malformation of the vertebrae. The aclampsia phenotype was caused by aberrant chondrocyte proliferation in the intervertebral discs that blocked endochondral ossification. Importantly, the disease pattern occurred in an inflammation-independent manner. Conclusion. Chronic activation of the Hh signal pathway in spinal chondrocytes can trigger an ankylosing spine morphology without immune cell contributions. Hence, the destruction of cartilage and loss of axial joint integrity can result from chondrocyte-intrinsic defects of monogenic origin. © 2013 American College of Rheumatology.
| Description | Download |
| Characteristic tail phenotype of Ptch1 mutant mice. | Supplementary Movie S1 |
| Tail stiffness of Ptch1 mutant mice (control). | Supplementary Movie S2 |
| Tail stiffness of Ptch1 mutant mice (mutant). | Supplementary Movie S3 |
| Spine pathology in adult Ptch1 mutant mice (control). | Supplementary Movie S4 |
| Spine pathology in adult Ptch1 mutant mice (mutant). | Supplementary Movie S5 |