Health consequences of mutant cartilage oligomeric matrix protein and its relationship to abnormal growth and joint degeneration

Hecht, Jacqueline; Chiu, Frankie; Veerisetty, Alka C.; Hossain, Mohammad; Posey, Karen L.

doi:10.1016/j.matbio.2023.03.008

Cited by 5 publications

(13 citation statements)

References 101 publications

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“…In order to study PSACH pathologic mechanisms and test therapeutics in vivo, we generated the MT-COMP mouse that expresses mutant human D469del-COMP (deletion of one of five consecutive aspartic acid residues) in tissues expressing type II collagen with doxycycline (DOX) administration. The expression of the most common PSACH mutation (D469del-COMP) in addition to the endogenous wild-type mouse COMP recapitulates the clinical phenotype and PSACH chondrocyte pathology in a mouse designated the MT-COMP [44]. The MT-COMP mouse allowed for us to demonstrate that accumulation of mutant-COMP in the rER (rough endoplasmic reticulum) due to misfolding is cytotoxic to chondrocytes in the growth plate and articular cartilage [38,45,46].…”

Section: Chondrocyte Pathology and Mechanismsmentioning

confidence: 95%

“…PSACH pain is described as tiring, exhausting, nagging, aching, throbbing, sharp, and miserable [50]. Joint pain and degenerative changes in the joints along with micro-injuries from extremely lax joints necessitate joint replacements in the late 20 ′ s [36,44]. Typically, hips are replaced first, followed by knees, and some individuals have shoulders and elbows replaced.…”

Section: Psach Painmentioning

confidence: 99%

“…MT-COMP mice joint degeneration studies demonstrate multiple sources of nociceptive pain present, including subchondral bone remodeling, meniscus damage, synovitis, and inflammation [27]. A non-surgical approach is desperately needed since all joints are affected, but not all joints are replaceable, and numerous years of uncontrolled pain are endured before joint replacement [38,44,50,51].…”

Section: Psach Painmentioning

confidence: 99%

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Curcumin and Resveratrol: Nutraceuticals with so Much Potential for Pseudoachondroplasia and Other ER-Stress Conditions

Posey

2024

Biomolecules

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Natural products with health benefits, nutraceuticals, have shown considerable promise in many studies; however, this potential has yet to translate into widespread clinical use for any condition. Notably, many drugs currently on the market, including the first analgesic aspirin, are derived from plant extracts, emphasizing the historical significance of natural products in drug development. Curcumin and resveratrol, well-studied nutraceuticals, have excellent safety profiles with relatively mild side effects. Their long history of safe use and the natural origins of numerous drugs contrast with the unfavorable reputation associated with nutraceuticals. This review aims to explore the nutraceutical potential for treating pseudoachondroplasia, a rare dwarfing condition, by relating the mechanisms of action of curcumin and resveratrol to molecular pathology. Specifically, we will examine the curcumin and resveratrol mechanisms of action related to endoplasmic reticulum stress, inflammation, oxidative stress, cartilage health, and pain. Additionally, the barriers to the effective use of nutraceuticals will be discussed. These challenges include poor bioavailability, variations in content and purity that lead to inconsistent results in clinical trials, as well as prevailing perceptions among both the public and medical professionals. Addressing these hurdles is crucial to realizing the full therapeutic potential of nutraceuticals in the context of pseudoachondroplasia and other health conditions that might benefit.

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Section: Chondrocyte Pathology and Mechanismsmentioning

confidence: 95%

Section: Psach Painmentioning

confidence: 99%

Section: Psach Painmentioning

confidence: 99%

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Curcumin and Resveratrol: Nutraceuticals with so Much Potential for Pseudoachondroplasia and Other ER-Stress Conditions

Posey

2024

Biomolecules

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“…核生物以及2502个病毒, 共5090个代表基因组的序列与直系同源组(Orthologous Groups, OG)信息 [34] . [41] . CTSB (Cathepsin B)和MRGPRX2…”

Section: 0数据库包含4445个细菌、168个古细菌、477个真unclassified

水熊虫耐干燥机制的关键分子筛选

Zheng,

Shen,

Hou

et al. 2024

Sci. Sin.-Vitae

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This research delves into the molecular mechanisms that allow tardigrades to survive extreme dehydration. We collected genome data of 3 tardigrade species and 11 other metazoa and used OrthoFinder to identify 4 expanded gene families in tardigrades. Multiple bioinformatics techniques were employed to annotate 12899 genes of Ramazzottius varieornatus and determine 5032 differentially expressed genes in the hydrated and various dehydrated states. Additionally, these DEGs were divided into 9 clusters by Fuzzy C-Means algorithms, and those showing upregulated expression during anhydrobiosis were further evaluated in terms of molecular functions. After all, we concluded that the enzyme UGT72E1 may help tardigrades enhance the tolerance to dehydration by participating in the phenylpropane metabolism. This finding was verified by another tardigrade species.

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“…In contrast, mutations in COMP cause pseudoachondroplasia (PSACH), a severe dwarfing condition characterized by disproportionately short stature, short limbs, joint laxity, pain, and early-onset joint degeneration [3,[8][9][10][11][12][13][14][15][16][17][18]. PSACH birth parameters are within the normal range, and the first noticeable change is linear growth deceleration starting around one year of life and a waddling gait that appears after two years [19]. Characteristic rhizomelic shortening of long bones, small abnormal and underossified epiphyses, widened and irregular metaphyses, and platyspondyly are the radiograph findings that confirm the diagnosis [13,17,19].…”

Section: Introductionmentioning

confidence: 99%

Early Resveratrol Treatment Mitigates Joint Degeneration and Dampens Pain in a Mouse Model of Pseudoachondroplasia (PSACH)

Hecht,

Veerisetty,

Patra

et al. 2023

Biomolecules

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Pseudoachondroplasia (PSACH), a severe dwarfing condition associated with early-onset joint degeneration and lifelong joint pain, is caused by mutations in cartilage oligomeric matrix protein (COMP). The mechanisms underlying the mutant-COMP pathology have been defined using the MT-COMP mouse model of PSACH that has the common D469del mutation. Mutant-COMP protein does not fold properly, and it is retained in the rough endoplasmic reticulum (rER) of chondrocytes rather than being exported to the extracellular matrix (ECM), driving ER stress that stimulates oxidative stress and inflammation, driving a self-perpetuating cycle. CHOP (ER stress signaling protein) and TNFα inflammation drive high levels of mTORC1 signaling, shutting down autophagy and blocking ER clearance, resulting in premature loss of chondrocytes that negatively impacts linear growth and causes early joint degeneration in MT-COMP mice and PSACH. Previously, we have shown that resveratrol treatment from birth to 20 weeks prevents joint degeneration and decreases the pathological processes in articular chondrocytes. Resveratrol’s therapeutic mechanism of action in the mutant-COMP pathology was shown to act by primarily stimulating autophagy and reducing inflammation. Importantly, we demonstrated that MT-COMP mice experience pain consistent with PSACH joint pain. Here, we show, in the MT-COMP mouse, that resveratrol treatment must begin within 4 weeks to preserve joint health and reduce pain. Resveratrol treatment started at 6 or 8 weeks (to 20 weeks) was not effective in preventing joint degeneration. Collectively, our findings in MT-COMP mice show that there is a postnatal resveratrol treatment window wherein the inevitable mutant-COMP joint degeneration and pain can be prevented.

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Health consequences of mutant cartilage oligomeric matrix protein and its relationship to abnormal growth and joint degeneration

Cited by 5 publications

References 101 publications

Curcumin and Resveratrol: Nutraceuticals with so Much Potential for Pseudoachondroplasia and Other ER-Stress Conditions

Curcumin and Resveratrol: Nutraceuticals with so Much Potential for Pseudoachondroplasia and Other ER-Stress Conditions

水熊虫耐干燥机制的关键分子筛选

Early Resveratrol Treatment Mitigates Joint Degeneration and Dampens Pain in a Mouse Model of Pseudoachondroplasia (PSACH)

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