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Differentiating Chondrocytes from Peripheral Blood-derived Human Induced Pluripotent Stem Cells
Published on: July 18, 2017
Mesencephalic astrocyte-derived neurotropic factor is an important factor in chondrocyte ER homeostasis
P A Bell1,2, E P Dennis1,3, C L Hartley3,4
1Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, UK.
Abstract:
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, Schmid type (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.
Insights
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is crucial for skeletal homeostasis. Its absence in cartilage induces endoplasmic reticulum stress, leading to chondrodysplasia-like phenotypes and impaired long bone growth.
Area of Science:
- Skeletal Biology
- Cellular Biology
- Molecular Medicine
Background:
- Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER-resident protein with cytoprotective roles.
- MANF is upregulated in skeletal diseases like MCDS and MED, suggesting a role in skeletal homeostasis.
- Its specific function in cartilage and skeletal development was previously unknown.
Purpose of the Study:
- To investigate the role of MANF in skeletal tissue homeostasis and its potential involvement in skeletal dysplasias.
- To determine if MANF's chondroprotective effects are linked to endoplasmic reticulum (ER) stress modulation.
- To elucidate the consequences of MANF ablation in cartilage on skeletal development.
Main Methods:
- Utilized a mouse model with cartilage-specific deletion of Manf (Col2Cre).
- Analyzed disease severity in a mouse model of multiple epiphyseal dysplasia (MED) with cartilage-specific Manf deletion.
- Assessed cellular levels of BiP (GRP78) and other ER-resident chaperones in response to MANF modulation.
- Evaluated chondrocyte apoptosis and proliferation, and long bone growth in Manf-ablated mice.
Main Results:
- Cartilage-specific deletion of Manf in MED mice exacerbated disease severity.
- Exogenous MANF reduced BiP levels in MED chondrocytes but did not resolve mutant matrilin-3 retention.
- Ablation of MANF in cartilage induced ER stress, evidenced by increased BiP and other chaperones.
- MANF deficiency in cartilage led to chondrodysplasia-like phenotypes, increased chondrocyte apoptosis, decreased proliferation, and reduced long bone growth.
Conclusions:
- Intracellular MANF, rather than extracellular, is critical for skeletal pathobiology.
- MANF deficiency in cartilage induces ER stress, which is sufficient to cause skeletal growth defects.
- ER stress is a key mechanism in skeletal dysplasias and represents a potential therapeutic target.
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