Mesencephalic astrocyte-derived neurotropic factor is an important factor in chondrocyte ER homeostasis

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. Electronic supplementary material The online version of this article (10.1007/s12192-018-0953-7) contains supplementary material, which is available to authorized users.

MANF Ablation Causes Prolonged Activation of the UPR without Neurodegeneration in the Mouse Midbrain Dopamine System

“…In contrast to global Manf -/mice in the ICR strain that die prematurely (Lindahl et al, 2014) and Manf -/mice in the C57BL/6 strain that are perinatal lethal (Neves et al, 2016;Bell et al, 2019), Manf fl/fl ::Nestin Cre/1 mice were viable and visibly similar to littermates when followed until the age of 18 months. The body weights of Manf fl/fl ::Nestin Cre/1 mice were reduced at four and 16 months of age compared with the Manf fl/fl controls but when comparing Manf fl/fl :: Nestin Cre/1 mice with Nestin Cre/1 mice, there was no difference in body weight ( Fig.…”

“…Previously it has been shown that loss of MANF in pancreatic b cells leads to chronic UPR activation in vivo (Lindahl et al, 2014). Recently, it was also demonstrated that ablation of MANF in cartilage results in upregulation of ER chaperones in vivo (Bell et al, 2019). Therefore, we examined the expression of UPR-related genes in the brains of both conventional Manf -/and conditional Manf fl/fl :: Nestin Cre/1 KO mice.…”

Deficiency of the ER-stress-regulator MANF triggers progressive outer hair cell death and hearing loss

“…Of note, both l-and s-group mutants showed other phenotypic changes typical to the Manf KO mice, namely hyperglycemia and reduced growth (Fig. 2f, g) 4,5 .…”

“…Analysis of the Manf loss-of-function mutant mice has shown that the insulin-producing beta cells of the pancreas are particularly sensitive to Manf deficiency; they die from the juvenile stages onward, leading to diabetes 4 . The mouse strain has an impact on the Manf knock out (KO) phenotype: KO mice under the C57BL/6J (BL6) background die perinatally due to respiratory problems, whereas most KOs under the CD-1 background survive to adulthood 4,5 . Thus, available data give evidence that MANF promotes cell survival in a cell context-dependent and genetic backgrounddependent fashion.…”

Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Is Highly Expressed in Mouse Tissues With Metabolic Function

“…A recent study has identified the importance of MANF for skeletal growth (59). Cartilage-specific ablation of Manf in mice led to skeletal dysplasias caused by reduced chondrocyte proliferation and increased ER stress.…”