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Lookup NU author(s): Dr Peter Bell, Dr Ella Dennis, Robert Jackson, Dr Anna Porter, Dr Katarzyna PirogORCiD, Professor Michael Briggs
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) resident protein that can be secreted due to an imperfect KDEL motif. MANF plays a cytoprotective role in several soft tissues and is upregulated in conditions resulting from intracellular retention of mutant protein, including two skeletal diseases, metaphyseal chondrodysplasia type Schmid (MCDS) and multiple epiphyseal dysplasia (MED). The role of MANF in skeletal tissue homeostasis is currently unknown. Interestingly, cartilage-specific deletion of Manf in a mouse model of MED resulted in increased disease severity, suggesting its upregulation may be chondroprotective. Treatment of MED chondrocytes with exogenous MANF led to a decrease in the cellular levels of BiP (GRP78), confirming MANF’s potential to modulate ER stress responses. However, it did not alleviate the intracellular retention of mutant matrilin-3, suggesting that it is the intracellular MANF that is of importance in the pathobiology of skeletal dysplasias. The Col2Cre-driven deletion of Manf from mouse cartilage resulted in a chondrodysplasia-like phenotype. Interestingly, ablation of MANF in cartilage did not have extracellular consequences, but led to an upregulation of several ER-resident chaperones including BiP. This apparent induction of ER-stress in turn led to dysregulated chondrocyte apoptosis and decreased proliferation, resulting in reduced long bone growth. We have previously shown that ER stress is an underlying disease mechanism for several skeletal dysplasias. The cartilage-specific deletion of Manf described in this study phenocopies our previously published chondrodysplasia models, further confirming that ER-stress itself is sufficient to disrupt skeletal growth and thus represents a potential therapeutic target.
Author(s): Bell PA, Dennis EP, Hartley CL, Jackson RM, Porter A, Boot-Handford RP, Pirog KA, Briggs MD
Publication type: Article
Publication status: Published
Journal: Cell Stress and Chaperones
Year: 2018
Volume: 24
Issue: 1
Pages: 159-173
Print publication date: 01/01/2019
Online publication date: 12/12/2018
Acceptance date: 23/11/2018
Date deposited: 29/11/2018
ISSN (print): 1355-8145
ISSN (electronic): 1466-1268
Publisher: Springer Netherlands
URL: https://doi.org/10.1007/s12192-018-0953-7
DOI: 10.1007/s12192-018-0953-7
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