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Inactivation of Patched1 in Murine Chondrocytes Causes Spinal Fusion Without Inflammation
Author(s) -
Dittmann Kai,
Wuelling Manuela,
Uhmann Anja,
Dullin Christian,
Hahn Heidi,
Schweyer Stefan,
Vortkamp Andrea,
Wienands Jürgen
Publication year - 2014
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.38325
Subject(s) - endochondral ossification , chondrocyte , indian hedgehog , patched , cartilage , ossification , microbiology and biotechnology , biology , pathology , hedgehog signaling pathway , anatomy , signal transduction , medicine
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 relationship to normal or pathogenic bone formation is unclear. This study was undertaken to establish a genetic tool that allows the discrete inactivation of genes in spinal chondrocytes, and to investigate in vivo how chondrocyte‐specific ablation of the inhibitory HH receptor Patched 1 ( Ptch1) affects skeleton integrity. Methods A Cre ‐deleter mouse strain, mb1‐Cre , for selective gene recombination in spinal chondrocytes was identified by in situ hybridization and histologic analysis. The mb1‐Cre +/− animals were crossed with mice that harbor a loxP‐flanked Ptch1 gene ( Ptch1 flox/flox ) to abrogate the inhibition of the HH signaling pathway in chondrocytes. The skeletal integrity of F1 mice was characterized by high‐resolution flat‐panel–based volume computed tomography and histologic staining procedures. Results During the first weeks after birth, all mb1‐Cre +/− / Ptch1 flox/flox mice developed progressive spinal fusion with malformation of the vertebrae. This 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 Our findings indicate that 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.