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Ubiquitin-dependent proteolysis of CXCL7 results in posterior longitudinal ligament ossification.

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Ubiquitin-dependent proteolysis of CXCL7 results in posterior longitudinal ligament ossification.

PLoS One. 2018;13(5):e0196204

Authors: Tsuru M, Ono A, Umeyama H, Takeuchi M, Nagata Okay

Summary
Ossification of the posterior longitudinal ligament (OPLL), a spinal ligament, reduces the vary of movement in limbs. No remedy is presently out there for OPLL, which is why therapies are urgently wanted. OPLL happens in weight problems, is extra widespread in males, and has an onset after 40 years of age. The mechanisms underlying OPLL stay unclear. On this examine, we carried out a serum proteomic evaluation in each OPLL sufferers and wholesome topics to establish components probably concerned within the improvement of OPLL, and located diminished ranges of a protein that may underlie the pathology of OPLL. We remoted the protein, decided its amino acid sequence, and recognized it as chemokine (C-X-C motif) ligand 7 (CXCL7). Primarily based on these proteomics findings, we generated a CXCL7 knockout mouse mannequin to review the molecular mechanisms underlying OPLL. CXCL7-null mice introduced with a phenotype of OPLL, exhibiting motor impairment, heterotopic ossification within the posterior ligament tissue, and osteoporosis in vertebrate tissue. To establish the mechanisms of CXCL7 deficiency in OPLL, we looked for single nucleotide polymorphisms and altered DNA exons, however no abnormalities had been discovered. Though miR-340 ranges had been discovered to be excessive in an miRNA array, they had been inadequate to scale back CXCL7 ranges. Ubiquitin C-terminal hydrolase1 (UCHL1) was discovered to be overexpressed in CXCL7-null mice and within the sera of sufferers with OPLL, and was correlated with OPLL severity. Publish-translational modifications of proteins with ubiquitin and ubiquitin-like modifiers, orchestrated by a cascade of specialised ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2), and ubiquitin ligase (E3) enzymes, are thought to manage a variety of mobile processes, and alterations within the ubiquitin-proteasome system have been related to a number of degenerative problems. As well as, the OPLL tissue of CXCL7-null mouse and its major cells expressed the antibody to ubiquitin (linkage-specific Okay48). Our knowledge clearly present decreased CXCL7 ranges in sufferers with OPLL, and that OPLL developed in mice missing CXCL7. Tumor necrosis issue receptor-associated issue (TRAF)6 expression was decreased in CXCL7-null mouse major cells. Moreover, Okay48 polyubiquitination was present in posterior longitudinal ligament ossified tissue and first cells from CXCL7-null mice. We carried out a phosphoproteomics evaluation in CXCL7-deficient mice and recognized elevated phosphorylation of mitogen-activated protein kinase kinase (ME3K)15, ubiquitin protein ligase E3C (UBE3C) and protein kinase C (PKC) alpha, suggesting that ubiquitin-dependent degradation is concerned in CXCL7 deficiency. Future research within the CXCL7-null mouse mannequin are, subsequently, warranted to research the function of ubiquitination within the onset of OPLL. In conclusion, CXCL7 ranges could also be helpful as a serum marker for the development of OPLL. This examine additionally means that growing CXCL7 ranges in sufferers can function an efficient therapeutic technique for the remedy of OPLL.

PMID: 29782494 [PubMed – in process]

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