Suppressing Chondrocyte Hypertrophy to Build Better Cartilage

Shigley, Christian; Trivedi, Jay; Meghani, Ozair; Owens, Brett D.; Jayasuriya, Chathuraka T.

doi:10.3390/bioengineering10060741

Cited by 3 publications

(4 citation statements)

References 157 publications

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“…Chondrocytes in the non-calcified zones of joint cartilage do not undergo hypertrophic phenotype alterations under normal conditions. However, OA-associated hypertrophic phenotype alterations in joint cartilage enhance pathological damage, such as calcification and vascularization (30,31). Inhibition of chondrocyte hypertrophy in joint cartilage exhibits potential as a therapeutic strategy for OA management (31).…”

Section: Discussionmentioning

confidence: 99%

“…However, OA-associated hypertrophic phenotype alterations in joint cartilage enhance pathological damage, such as calcification and vascularization (30,31). Inhibition of chondrocyte hypertrophy in joint cartilage exhibits potential as a therapeutic strategy for OA management (31). At present, numerous studies on the pathogenesis of OA are focused on inflammatory responses.…”

Section: Discussionmentioning

confidence: 99%

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TMF suppresses chondrocyte hypertrophy in osteoarthritic cartilage by mediating the FOXO3a/BMPER pathway

Huang,

Ren,

Jiao

et al. 2024

Exp Ther Med

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Osteoarthritis (OA) is a disease of the joints, characterized by chronic inflammation, cartilage destruction and extracellular matrix (ECM) remodeling. Aberrant chondrocyte hypertrophy promotes cartilage destruction and OA development. Collagen X, the biomarker of chondrocyte hypertrophy, is upregulated by runt-related transcription factor 2 (Runx2), which is mediated by the bone morphogenetic protein 4 (BMP4)/Smad1 signaling pathway. BMP binding endothelial regulator (BMPER), a secreted glycoprotein, acts as an agonist of BMP4. 5,7,3',4'-tetramethoxyflavone (TMF) is a natural flavonoid derived from Murraya exotica L. Results of our previous study demonstrated that TMF exhibits chondroprotective effects against OA development through the activation of Forkhead box protein O3a (FOXO3a) expression. However, whether TMF suppresses chondrocyte hypertrophy through activation of FOXO3a expression and inhibition of BMPER/BMP4/ Smad1 signaling remains unknown. Results of the present study revealed that TMF inhibited collagen X and Runx2 expression, inhibited BMPER/BMP4/Smad1 signaling, and activated FOXO3a expression; thus, protecting against chondrocyte hypertrophy and OA development. However, BMPER overexpression and FOXO3a knockdown impacted the protective effects of TMF. Thus, TMF inhibited chondrocyte hypertrophy in OA cartilage through mediating the FOXO3a/BMPER signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

TMF suppresses chondrocyte hypertrophy in osteoarthritic cartilage by mediating the FOXO3a/BMPER pathway

Huang,

Ren,

Jiao

et al. 2024

Exp Ther Med

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“…Acute cartilage trauma is known to cause hypertrophic chondrocyte differentiation and chondrocyte death [15,16,18]. Therefore, it was hypothesised that minced cartilage would exhibit the typical characteristics of chondrocyte hypertrophy seen in traumatised cartilage [12].…”

Section: Discussionmentioning

confidence: 99%

“…These changes in the molecular composition and cleavage of collagens result in a loss of cartilage extracellular matrix [19]. It is therefore important for a successful regenerative treatment to prevent the differentiation of chondrocytes towards hypertrophy [16].…”

Section: Introductionmentioning

confidence: 99%

Collagen 1 gel may improve the regenerative capacity of minced adult and preosteoarthritic cartilage

Jahn,

Halm‐Pozniak,

Klutzny

et al. 2024

Knee surg. sports traumatol. arthrosc.

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PurposeMinced cartilage implantation (MCI) is an evolving technique for the treatment of osteochondral lesions. It was hypothesised that mincing of cartilage may affect chondrocyte viability and phenotype and that embedding in collagen 1 gel results in an improved outcome. The objective of this study was to evaluate the impact of cartilage mincing and whether collagen 1 gel mediates beneficial effects on the chondrocyte phenotype and viability.MethodsHuman cartilage samples from 11 patients undergoing total knee arthroplasty were collected and minced according to the MCI protocol. Minced cartilage was cultured for 1 week with and without embedding in collagen 1 gel and was compared with unminced cartilage flakes as control. Quantitative reverse transcription‐PCR and immunohistochemical staining for the chondrocyte marker genes SOX9, COL2, ACAN, COL10 and MMP13 were used to examine the chondrocyte phenotype. Cell death was assessed by the terminal deoxynucleotidyl transferase dUTP nick‐end labeling assay.ResultsIncreased chondrocyte cell death of cultured cartilage after mincing was observed. Chondrocytes from minced cartilage exhibited significantly decreased expression and protein levels of homeostatic and hypertrophic chondrocyte markers. Embedding in collagen 1 gel showed no positive effect on viability. However, remarkable is the increased expression of ACAN and the preserved protein level of SOX9 in the collagen 1‐embedded minced cartilage.ConclusionsThis study shows that the mincing of cartilage leads to increased chondrocyte death and decreased expression of chondrocyte phenotypic marker genes after 7 days. The use of collagen 1 gel may improve the stability of the phenotype, which needs to be further elucidated.Level of EvidenceLevel III (therapeutic).

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Cinnamaldehyde-Treated Bone Marrow Mesenchymal-Stem-Cell-Derived Exosomes via Aqueous Two-Phase System Attenuate IL-1β-Induced Inflammation and Catabolism via Modulation of Proinflammatory Signaling Pathways

Sankaranarayanan,

Lee,

Kim

et al. 2024

IJMS

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Osteoarthritis (OA) is a degenerative joint disorder that is distinguished by inflammation and chronic cartilage damage. Interleukin-1β (IL-1β) is a proinflammatory cytokine that plays an important role in the catabolic processes that underlie the pathogenesis of OA. In this study, we investigate the therapeutic efficacy of exosomes derived from untreated bone-marrow-derived mesenchymal stem cells (BMMSC-Exo) and those treated with cinnamaldehyde (BMMSC-CA-Exo) for preventing the in vitro catabolic effects of IL-1β on chondrocytes. We stimulated chondrocytes with IL-1β to mimic the inflammatory microenvironment of OA. We then treated these chondrocytes with BMMSC-Exo and BMMSC-CA-Exo isolated via an aqueous two-phase system and evaluated their effects on the key cellular processes using molecular techniques. Our findings revealed that treatment with BMMSC-Exo reduces the catabolic effects of IL-1β on chondrocytes and alleviates inflammation. However, further studies directly comparing treatments with BMMSC-Exo and BMMSC-CA-Exo are needed to determine if CA preconditioning can provide additional anti-inflammatory benefits to the exosomes beyond those of CA preconditioning or treatment with regular BMMSC-Exo. Through a comprehensive molecular analysis, we elucidated the regulatory mechanisms underlying this protective effect. We found a significant downregulation of proinflammatory signaling pathways in exosome-infected chondrocytes, suggesting the potential modulation of the NF-κB and MAPK signaling cascades. Furthermore, our study identified the molecular cargo of BMMSC-Exo and BMMSC-CA-Exo, determining the key molecules, such as anti-inflammatory cytokines and cartilage-associated factors, that may contribute to their acquisition of chondroprotective properties. In summary, BMMSC-Exo and BMMSC-CA-Exo exhibit the potential as therapeutic agents for OA by antagonizing the in vitro catabolic effects of IL-1β on chondrocytes. The regulation of the proinflammatory signaling pathways and bioactive molecules delivered by the exosomes suggests a multifaceted mechanism of action. These findings highlight the need for further investigation into exosome-based therapies for OA and joint-related diseases.

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Suppressing Chondrocyte Hypertrophy to Build Better Cartilage

Cited by 3 publications

References 157 publications

TMF suppresses chondrocyte hypertrophy in osteoarthritic cartilage by mediating the FOXO3a/BMPER pathway

TMF suppresses chondrocyte hypertrophy in osteoarthritic cartilage by mediating the FOXO3a/BMPER pathway

Collagen 1 gel may improve the regenerative capacity of minced adult and preosteoarthritic cartilage

Cinnamaldehyde-Treated Bone Marrow Mesenchymal-Stem-Cell-Derived Exosomes via Aqueous Two-Phase System Attenuate IL-1β-Induced Inflammation and Catabolism via Modulation of Proinflammatory Signaling Pathways

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