Calcium-phosphate complex increased during subchondral bone remodeling affects earlystage osteoarthritis

Jung, Youn‐Kwan; Han, Min-Su; Park, Hyeri; Lee, Eun‐Ju; Jang, Ji-Ae; Kim, Gun-Woo; Lee, Sun-Young; Moon, DaeWon; Han, Seung-Woo

doi:10.1038/s41598-017-18946-y

Cited by 28 publications

(22 citation statements)

References 43 publications

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“…Next, we tested if the breakdown products of chondroitin-sulfate can function as damage-associated molecular patterns (DAMPs) that can be responsible for the increase of proteases and oxidative stress. In the preceding study, we confirmed that the ligands for TLR2 and TLR4 significantly involves in the expression of MMP-3 and MMP-13 in chondrocytes 21 . On this basis, we inhibited the function of TLR2 and TLR4 with OxPAPC, a dual TLR2 and TLR4 inhibitor or LPS-RS, a functional TLR4 inhibitor through MD2 inhibition, and assessed the chondrocyte phenotype by chondroitinase treatment.…”

Section: Resultssupporting

confidence: 78%

Degrading products of chondroitin sulfate can induce hypertrophy-like changes and MMP-13/ADAMTS5 production in chondrocytes

Jung

Park

Cho

et al. 2019

Sci Rep

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Chondroitin sulfate (CS) is the most abundant glycosaminoglycan (GAG) in articular cartilage and the loss of CS-GAG occurs early in OA. As a major component of perichondral matrix interacting directly with chondrocytes, the active turnover of CS can affect to break the homeostasis of chondrocytes. Here we employ CS-based 3-dimensional (3D) hydrogel scaffold system to investigate how the degradation products of CS affect the catabolic phenotype of chondrocytes. The breakdown of CS-based ECM by the chondroitinase ABC (ChABC) resulted in a hypertrophy-like morphologic change in chondrocytes, which was accompanied by catabolic phenotypes, including increased MMP-13 and ADAMTS5 expression, nitric oxide (NO) production and oxidative stress. The inhibition of Toll-like receptor 2 (TLR2) or TLR4 with OxPAPC (TLR2 and TLR4 dual inhibitor) and LPS-RS (TLR4-MD2 inhibitor) ameliorated these catabolic phenotypes of chondrocytes by CS-ECM degradation, suggesting a role of CS breakdown products as damage-associated molecular patterns (DAMPs). As downstream signals of TLRs, MAP kinases, NF-kB, NO and STAT3-related signals were responsible for the catabolic phenotypes of chondrocytes associated with ECM degradation. NO in turn reinforced the activation of MAP kinases as well as NFkB signaling pathway. Thus, these results propose that the breakdown product of CS-GAG can recapitulate the catabolic phenotypes of OA.

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Section: Resultssupporting

confidence: 78%

Degrading products of chondroitin sulfate can induce hypertrophy-like changes and MMP-13/ADAMTS5 production in chondrocytes

Jung

Park

Cho

et al. 2019

Sci Rep

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“…1 ). The activation of osteoclasts in the early stage of OA induces active remodelling of subchondral bone 12 , 18 . This process can release matrix-derived coupling factors, such as Insulin-like growth factor 1 (IGF-1) and TGFβ, and the inhibition of TGFβ in subchondral bone can attenuate the progression of surgically induced OA 19 .…”

Section: Discussionmentioning

confidence: 99%

“…Our study provides a possible explanation for the catabolic function of TGFβ via TG2 in subchondral bone. Active subchondral bone remodelling during early OA can increase both TGFβ and calcium levels in the subchondral milieu 12 . TGFβ can increase the expression of TG2 in hypertrophic chondrocytes in the neighbouring subchondral bone 9 , and this calcium-rich environment in subchondral bone may enhance the calcium-dependent enzyme activity of TG2.…”

Section: Discussionmentioning

confidence: 99%

“…Surgical OA was induced by destabilization of the medial meniscus (DMM) in mice as previously described 12 . Briefly, after 12-week-old C57BL/6 male mice were anaesthetized, the skin over the left knee was opened, and the meniscotibial ligament of the medial meniscus was sectioned in total 15 mice among which 5 mice were sacrificed at 4 weeks without treatment, and 5 mice were treated with ZDON and 5 with control DMSO for 8 weeks.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we reported that enhanced subchondral bone remodelling in early OA can increase the calcium level in articular cartilage, and this change was related to MMP-3 and MMP-13 production 12 . This increased calcium level in the articular cartilage of early OA can affect the enzyme activity of TG2, which may affect the production and stability of MMPs, and consequently accelerate cartilage degradation.…”

Section: Introductionmentioning

confidence: 99%

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Transglutaminase-2 regulates Wnt and FoxO3a signaling to determine the severity of osteoarthritis

Han

Jung

Kim

et al. 2020

Sci Rep

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Transglutaminase 2 (TG2), also known as tissue transglutaminase, is a calcium-dependent enzyme that has a variety of intracellular and extracellular substrates. TG2 not only increases in osteoarthritis (OA) tissue but also affects the progression of OA. However, it is still unclear how TG2 affects cartilage degradation in OA at the molecular level. Surgically induced OA lead to an increase of TG2 in the articular cartilage and growth plate, and it was dependent on TGFβ1 in primary chondrocytes. The inhibition of TG2 enzymatic activity with intra-articular injection of ZDON, the peptide-based specific TG2 inhibitor, ameliorated the severity of surgically induced OA as well as the expression of MMP-3 and MMP-13. ZDON attenuated MMP-3 and MMP-13 expression in TGFβ- and calcium ionophore-treated chondrocytes in a Runx2-independent manner. TG2 inhibition with ZDON suppressed canonical Wnt signaling through a reduction of β-catenin, which was mediated by ubiquitination-dependent proteasomal degradation. In addition, TG2 activation by a calcium ionophore enhanced the phosphorylation of AMPK and FoxO3a and the nuclear translocation of FoxO3a, which was responsible for the increase in MMP-13. In conclusion, TG2 plays an important role in the pathogenesis of OA as a major catabolic mediator that affects the stability of β-catenin and FoxO3a-mediated MMP-13 production.

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Contrast‐enhanced micro‐computed tomography of compartment and time‐dependent changes in femoral cartilage and subchondral plate in a murine model of osteoarthritis

Chan

Mashiatulla

et al. 2022

The Anatomical Record

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A lack of understanding of the mechanisms underlying osteoarthritis (OA) progression limits the development of effective long‐term treatments. Quantitatively tracking spatiotemporal patterns of cartilage and bone degeneration is critical for assessment of more appropriately targeted OA therapies. In this study, we use contrast‐enhanced micro‐computed tomography (μCT) to establish a timeline of subchondral plate (SCP) and cartilage changes in the murine femur after destabilization of the medial meniscus (DMM). We performed DMM or sham surgery in 10–12‐week‐old male C57Bl/6J mice. Femora were imaged using μCT after 0, 2, 4, or 8 weeks. Cartilage‐optimized scans were performed after immersion in contrast agent CA4+. Bone mineral density distribution (BMDD), cartilage attenuation, SCP, and cartilage thickness and volume were measured, including lateral and medial femoral condyle and patellar groove compartments. As early as 2 weeks post‐DMM, cartilage thickness significantly increased and cartilage attenuation, SCP volume, and BMDD mean significantly decreased. Trends in cartilage and SCP metrics within each joint compartment reflected those seen in global measurements, and both BMDD and SCP thickness were consistently greater in the lateral and medial condyles than the patellar groove. Sham surgery also resulted in significant changes to SCP and cartilage metrics, highlighting a potential limitation of using surgical models to study tissue morphology or composition changes during OA progression. Contrast‐enhanced μCT analysis is an effective tool to monitor changes in morphology and composition of cartilage, and when combined with bone‐optimized μCT, can be used to assess the progression of degenerative changes after joint injury.

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Calcium-phosphate complex increased during subchondral bone remodeling affects earlystage osteoarthritis

Cited by 28 publications

References 43 publications

Degrading products of chondroitin sulfate can induce hypertrophy-like changes and MMP-13/ADAMTS5 production in chondrocytes

Degrading products of chondroitin sulfate can induce hypertrophy-like changes and MMP-13/ADAMTS5 production in chondrocytes

Transglutaminase-2 regulates Wnt and FoxO3a signaling to determine the severity of osteoarthritis

Contrast‐enhanced micro‐computed tomography of compartment and time‐dependent changes in femoral cartilage and subchondral plate in a murine model of osteoarthritis

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