Novel therapeutic interventions for pseudoachondroplasia

Posey, Karen L.; Hecht, Jacqueline

doi:10.1016/j.bone.2017.03.045

Cited by 25 publications

(24 citation statements)

References 91 publications

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“…So far there is no special therapy for this genetic disease, only symptomatic treatments have been available for the affected individuals. 28 Of course, if there are spinal cord compression, severe osteoarthritis or severe osteoarticular deformity, surgical operation required. It was confirmed that growth hormone can do nothing about the short stature of PSACH patients.…”

Section: Discussionmentioning

confidence: 99%

A novel mutation in exon 11 of COMP gene in a Chinese family with pseudoachondroplasia

Zhang

et al. 2019

Genes & Diseases

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Pseudoachondroplasia (PSACH) is a relatively common skeletal dysplasia characterized by disproportionate short stature, joint laxity, early-onset osteoarthrosis, and dysplasia of the spine, epiphysis, and metaphysis. It is known as an autosomal dominant disease which results exclusively from mutations in the gene for Cartilage Oligomeric Matrix Protein (COMP). We have identified a five year old Chinese boy who was diagnosed as pseudoachondroplasia according to clinical manifestations and X-ray symptoms. His mother seems like another effected individual because of the apparent short stature. Genomic DNA was extracted from peripheral blood lymphocytes. DNA sequencing analysis of the COMP gene revealed a heterozygous mutation (c.1219 T > C,p.Cys407Arg) in the patient. His mother was also affected with the same genetic change. Mutations in COMP gene is proved to change the Cartilage Oligomeric Matrix Protein. This missense mutation (c.1219 T > C) has not been reported before and it is not belongs to polymorphism sites. Our results extend the spectrum of mutations in COMP gene leading to pseudoachondroplasia.

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Section: Discussionmentioning

confidence: 99%

A novel mutation in exon 11 of COMP gene in a Chinese family with pseudoachondroplasia

Zhang

et al. 2019

Genes & Diseases

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“…Moreover, we demonstrated that retention of COMP in the ER allows for the assembly of an ordered matrix within ER vesicles of MT-COMP mice (7) . Once an intracellular matrix forms, there are no degradative enzymes to break up this large complex, which is likely too large to be translocated out of the ER to the proteasome for degradation (12) . Importantly, the exciting findings from these studies show that there is a post-diagnosis window in which resveratrol diminishes growth plate pathology and clears mutant-COMP from the ER in MT-COMP mice.…”

Section: Treatment Of Mt-comp Mice With Resveratrol Reactivates Autopmentioning

confidence: 99%

“…It has long been known that mutant protein accumulates in PSACH chondrocytes (9)(10)(11) , mutations in COMP were shown to cause PSACH (10,11) . It was subsequently shown that mutant-COMP misfolds in the ER and prematurely assembles an ordered matrix involving types 2 and 9 collagens, matrilin 3 and other extracellular proteins, resulting in massive intracellular protein accumulation (7,8,12) . The protein accumulation in the ER of chondrocytes initiates a self-perpetuating pathological loop between oxidative stress, inflammation and ER stress that leads to elevated mTORC1 signaling, DNA damage and death of chondrocytes (4)(5)(6)13) .…”

Section: Introductionmentioning

confidence: 99%

Resveratrol Reduces COMPopathy in Mice Through Activation of Autophagy

et al. 2021

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Misfolding mutations in cartilage oligomeric matrix protein (COMP) cause it to be retained within the endoplasmic reticulum (ER) of chondrocytes, stimulating a multitude of damaging cellular responses including ER stress, inflammation, and oxidative stress, which ultimately culminates in the death of growth plate chondrocytes and pseudoachondroplasia (PSACH). Previously, we demonstrated that an antioxidant, resveratrol, substantially reduces the intracellular accumulation of mutant-COMP, dampens cellular stress, and lowers the level of growth plate chondrocyte death. In addition, we showed that resveratrol reduces mammalian target of rapamycin complex 1 (mTORC1) signaling, suggesting a potential mechanism. In this work, we investigate the role of autophagy in treatment of COMPopathies. In cultured chondrocytes expressing wild-type COMP or mutant-COMP, resveratrol significantly increased the number of Microtubule-associated protein 1A/1B-light chain 3 (LC3) vesicles, directly demonstrating that resveratrol-stimulated autophagy is an important component of the resveratrol-driven mechanism responsible for the degradation of mutant-COMP. Moreover, pharmacological inhibitors of autophagy suppressed degradation of mutant-COMP in our established mouse model of PSACH. In contrast, blockage of the proteasome did not substantially alter resveratrol clearance of mutant-COMP from growth plate chondrocytes. Mechanistically, resveratrol increased SIRT1 and PP2A expression and reduced MID1 expression and activation of phosphorylated protein kinase B (pAKT) and mTORC1 signaling in growth plate chondrocytes, allowing clearance of mutant-COMP by autophagy. Importantly, we show that optimal reduction in growth plate pathology, including decreased mutant-COMP retention, decreased mTORC1 signaling, and restoration of chondrocyte proliferation was attained when treatment was initiated between birth to 1 week of age in MT-COMP mice, translating to birth to approximately 2 years of age in children with PSACH. These results clearly demonstrate that resveratrol stimulates clearance of mutant-COMP by an autophagy-centric mechanism.

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“…Moreover, we demonstrated that retention of COMP in the ER allows for the assembly of an ordered matrix within ER vesicles of MT-COMP mice (7) . Once an intracellular matrix forms, there are no degradative enzymes to break up this large complex, which is likely too large to be translocated out of the ER to the proteasome for degradation (13) . Importantly, the exciting findings from these studies show that there is a post-diagnosis window in which resveratrol diminishes growth plate pathology and clears mutant COMP from the ER in MT-COMP mice.…”

Section: Resveratrol's Multifocal Targeted Mechanisms Of Action Is Shmentioning

confidence: 99%

“…It has long been known that mutant protein accumulates in PSACH chondrocytes (9)(10)(11) , mutations in COMP were shown to cause PSACH (10,11) . It was subsequently shown that mutant COMP misfolds in the ER and prematurely assembles an ordered matrix involving types 2 and 9 collagens, matrilin 3 and other extracellular proteins, resulting in massive intracellular protein accumulation (7,12,13) . The protein accumulation in the ER of chondrocytes initiates a self-perpetuating pathological loop between oxidative stress, inflammation and ER stress that leads to elevated mTORC1 signaling, DNA damage and death of chondrocytes (4)(5)(6)14) .…”

Section: Introductionmentioning

confidence: 99%

Resveratrol reduces COMPopathy in mice through activation of autophagy

Hecht

Coustry

Veerisetty

et al. 2020

Preprint

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Misfolding mutations in cartilage oligomeric matrix protein (COMP) cause it to be retained within in ER of chondrocytes, stimulating a multitude of damaging cellular responses including ER stress, inflammation and oxidative stress which ultimately culminates in the death of growth plate chondrocytes and pseudoachondroplasia (PSACH). Previously, we demonstrated that an antioxidant, resveratrol, substantially reduces the intracellular accumulation of mutant COMP, dampens cellular stress and lowers the level of growth plate chondrocyte death. In addition, we showed that resveratrol reduces mTORC1 (mammalian target of rapamycin complex 1) signaling, suggesting a potential mechanism. In this work, we investigate the role of autophagy in treatment of COMPopathies. In cultured chondrocytes expressing wild type or mutant COMP (MT-COMP), resveratrol significantly increased the number of large LC3 vesicles, directly demonstrating that resveratrol stimulated autophagy is an important component of the resveratrol-driven mechanism responsible for the degradation of mutant COMP. Moreover, pharmacological inhibitors of autophagy suppressed degradation of MT-COMP in our established mouse model of PSACH. In contrast, blockage of the proteasome did not substantially alter resveratrol clearance of mutant COMP from growth plate chondrocytes. Mechanistically, resveratrol increased SIRT1 and PP2A expression and reduced MID1 expression and activation of pAKT and mTORC1 signaling in growth plate chondrocytes, allowing clearance of mutant COMP by autophagy. Importantly, we show that optimal reduction in growth plate pathology, including decreased mutant COMP retention, decreased mTORC1 signaling and restoration of chondrocyte proliferation was attained when treatment was initiated between birth to one week of age in MT-COMP mice, translating to birth to approximately 2 years of age in PSACH children. These results clearly demonstrate that resveratrol stimulates clearance of mutant COMP by an autophagy-centric mechanism. Key Words: pseudoachondroplasia, autophagy, resveratrol, dwarfism, cartilage oligomeric matrix protein (COMP), proteasome, mTORC1

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Novel therapeutic interventions for pseudoachondroplasia

Cited by 25 publications

References 91 publications

A novel mutation in exon 11 of COMP gene in a Chinese family with pseudoachondroplasia

A novel mutation in exon 11 of COMP gene in a Chinese family with pseudoachondroplasia

Resveratrol Reduces COMPopathy in Mice Through Activation of Autophagy

Resveratrol reduces COMPopathy in mice through activation of autophagy

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