Erratum: Wnt/β-catenin signaling stimulates matrix catabolic genes and activity in articular chondrocytes: its possible role in joint degeneration

Osteoarthritis (OA) is a joint degenerative disease that is an exceedingly common problem associated with aging. Aging is the principal risk factor for OA, but damage-related physiopathology of articular chondrocytes probably drives the mechanisms of joint degeneration by a progressive decline in the homeostatic and regenerative capacity of cells. Cellular aging is the manifestation of a complex interplay of cellular and molecular pathways underpinned by transcriptional, translational, and epigenetic mechanisms and niche factors, and unraveling this complexity will improve our understanding of underlying molecular changes that affect the ability of the articular cartilage to maintain or regenerate itself. This insight is imperative for developing new cell and drug therapies for OA disease that will target the specific causes of age-related functional decline. This review explores the key age-related changes within articular chondrocytes and discusses the molecular mechanisms that are commonly perturbed as cartilage ages and degenerates. Current efforts and emerging potential therapies in treating OA that are being employed to halt or decelerate the aging processes are also discussed.

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Joint Degeneration in a Mouse Model of Pseudoachondroplasia: ER Stress, Inflammation, and Block of Autophagy

International Journal of Molecular Sciences ◽

10.3390/ijms22179239 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9239

Author(s):

Jacqueline T. Hecht ◽

Alka C. Veerisetty ◽

Mohammad G. Hossain ◽

Debabrata Patra ◽

Frankie Chiu ◽

...

Keyword(s):

Er Stress ◽

Matrix Protein ◽

Articular Chondrocytes ◽

Joint Degeneration ◽

Articular Chondrocyte ◽

Major Mechanism ◽

Chondrocyte Death ◽

Joint Health ◽

Degradative Enzymes ◽

Cellular Stresses

Pseudoachondroplasia (PSACH), a short limb skeletal dysplasia associated with premature joint degeneration, is caused by misfolding mutations in cartilage oligomeric matrix protein (COMP). Here, we define mutant-COMP-induced stress mechanisms that occur in articular chondrocytes of MT-COMP mice, a murine model of PSACH. The accumulation of mutant-COMP in the ER occurred early in MT-COMP articular chondrocytes and stimulated inflammation (TNFα) at 4 weeks, and articular chondrocyte death increased at 8 weeks while ER stress through CHOP was elevated by 12 weeks. Importantly, blockage of autophagy (pS6), the major mechanism that clears the ER, sustained cellular stress in MT-COMP articular chondrocytes. Degeneration of MT-COMP articular cartilage was similar to that observed in PSACH and was associated with increased MMPs, a family of degradative enzymes. Moreover, chronic cellular stresses stimulated senescence. Senescence-associated secretory phenotype (SASP) may play a role in generating and propagating a pro-degradative environment in the MT-COMP murine joint. The loss of CHOP or resveratrol treatment from birth preserved joint health in MT-COMP mice. Taken together, these results indicate that ER stress/CHOP signaling and autophagy blockage are central to mutant-COMP joint degeneration, and MT-COMP mice joint health can be preserved by decreasing articular chondrocyte stress. Future joint sparing therapeutics for PSACH may include resveratrol.

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Silymarin modulates catabolic cytokine expression through Sirt1 and SOX9 in human articular chondrocytes

Journal of Orthopaedic Surgery and Research ◽

10.1186/s13018-021-02305-9 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Wen-Tien Wu ◽

Yi-Ru Chen ◽

Dai-Hua Lu ◽

Fedor Svyatoslavovich Senatov ◽

Kai-Chiang Yang ◽

...

Keyword(s):

Protein Production ◽

Articular Chondrocytes ◽

Therapeutic Potential ◽

Early Stage ◽

Tissue Inhibitor Of Metalloproteinase ◽

Mitochondrial Activity ◽

High Dose ◽

Therapeutic Effects ◽

Mrna Levels ◽

Catabolic Genes

Abstract Background Silymarin (SMN), a polyphenolic flavonoid, is involved in multiple bioactive functions including anti-inflammation. Pretreatment with SMN demonstrated chondroprotection against tumour necrosis factor-alpha (TNF-α) stimulation in a chondrocyte cell line. However, pre- and posttreatment with phytochemicals have varying effects on osteoarthritis (OA) chondrocytes, and the therapeutic potential of SMN after catabolic cytokine stimulation is not fully elucidated. Methods The cytotoxicity of SMN (12.5, 25, 50 and 100 μM) was evaluated in human primary chondrocytes. The chondrocytes were supplemented with SMN (25 and 50 μM) after interleukin-1beta (IL-1β) stimulation. The mRNA expression and protein production of catabolic/anabolic cytokines as well as extracellular matrix (ECM) components were evaluated. Results High-dose SMN (100 μM) impaired the mitochondrial activity in chondrocytes, and 50 μM SMN further caused cell death in IL-1β-stimulated cells. The addition of 25 μM SMN ameliorated cell senescence; downregulated the catabolic genes of inducible nitric oxide synthase, IL-1β, TNF-α, matrix metalloproteinase-3 (MMP-3), MMP-9 and MMP-13; upregulated the anabolic genes of tissue inhibitor of metalloproteinase-1 (TIMP-1) and collagen type II alpha 1; and restored the expression of chondrogenic phenotype genes SOX9 and sirtuin-1 (Sirt1). In addition, the production of IL-1β, MMP-3 and MMP-9 decreased with an increase in TIMP-1 secretion. However, the mRNA levels of IL-6, IL-8 and IL-10 and protein production remained high. The addition of nicotinamide, a Sirt1 inhibitor, downregulated SOX9 and attenuated the therapeutic effects of SMN on IL-1β-stimulated chondrocytes. Conclusion SMN regulates the chondrocyte phenotype through Sirt1 and SOX9 to improve ECM homeostasis and may serve as a complementary therapy for early-stage knee OA.

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Joint degeneration in a mouse model of pseudoachondroplasia: ER stress, inflammation and autophagy blockage

10.1101/2021.06.04.447121 ◽

2021 ◽

Author(s):

Jacqueline T Hecht ◽

Alka C Veerisetty ◽

Mohammad G Hossain ◽

Debabrata Patra ◽

Frankie Chiu ◽

...

Keyword(s):

Er Stress ◽

Matrix Protein ◽

Articular Chondrocytes ◽

Joint Degeneration ◽

Articular Chondrocyte ◽

Major Mechanism ◽

Chondrocyte Death ◽

Joint Health ◽

Degradative Enzymes ◽

Cellular Stresses

Pseudoachondroplasia (PSACH), a short limb skeletal dysplasia, associated with premature joint degeneration is caused by misfolding mutations in cartilage oligomeric matrix protein (COMP). Here, we define mutant-COMP-induced stress mechanisms that occur in articular chondrocytes of MT-COMP mice, a murine model of PSACH. The accumulation of mutant-COMP in the ER occurred early in MT-COMP articular chondrocytes and stimulated inflammation (TNFα) at 4 wks. Articular chondrocyte death increased at 8 wks and ER stress through CHOP was elevated by 12 wks. Importantly, blockage of autophagy (pS6), the major mechanism which clears the ER, sustained cellular stress in MT-COMP articular chondrocytes. Degeneration of MT-COMP articular cartilage was similar to that observed in PSACH and was associated with increased MMPs, degradative enzymes. Moreover, chronic cellular stresses stimulated senescence. Senescence-associated secretory phenotype (SASP) may play a role in generating and propagating a pro-degradative environment in the MT-COMP murine joint. The loss of CHOP or resveratrol treatment from birth preserved joint health in MT-COMP mice. Taken together, these results indicate that ER stress/CHOP signaling and autophagy blockage are central to mutant-COMP joint degeneration and MT-COMP mice joint health can be preserved by decreasing articular chondrocyte stress. Future joint sparing therapeutics for PSACH may include resveratrol.

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