Conditional knockdown of hyaluronidase 2 in articular cartilage stimulates osteoarthritic progression in a mice model

Higuchi, Yoshitoshi; Nishida, Yoshihiro; Kozawa, Eiji; Zhuo, Lisheng; Arai, Eisuke; Hamada, Shunsuke; Morita, Daigo; Ikuta, Kazunari; Kimata, Koji; Ushida, Takahiro; Ishiguro, Naoki

doi:10.1038/s41598-017-07376-5

Cited by 13 publications

(10 citation statements)

References 42 publications

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“…Hyals can also cleave bigger size hyaluronic acid to alter the organization and stability of aggrecan. This idea is supported by the observation that Hyal2 deficient mice show cartilage development disorders and osteoarthritic like cartilage degeneration [30]. We demonstrated that Hyal2 and Hyal3 protein expression reduced on days of chondrogenic differentiation, while Hyal4 was elevated and Hyal1 was not altered on these days.…”

Section: Discussionsupporting

confidence: 72%

Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) Reduces Oxidative and Mechanical Stress-Evoked Matrix Degradation in Chondrifying Cell Cultures

Szentléleky

Szegeczki

Karanyicz

et al. 2019

IJMS

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Pituitary adenylate cyclase activating polypeptide (PACAP) is an endogenous neuropeptide also secreted by non-neural cells, including chondrocytes. PACAP signaling is involved in the regulation of chondrogenesis, but little is known about its connection to matrix turnover during cartilage formation and under cellular stress in developing cartilage. We found that the expression and activity of hyaluronidases (Hyals), matrix metalloproteinases (MMP), and aggrecanase were permanent during the course of chondrogenesis in primary chicken micromass cell cultures, although protein levels changed daily, along with moderate and relatively constant enzymatic activity. Next, we investigated whether PACAP influences matrix destructing enzyme activity during oxidative and mechanical stress in chondrogenic cells. Exogenous PACAP lowered Hyals and aggrecanase expression and activity during cellular stress. Expression and activation of the majority of cartilage matrix specific MMPs such as MMP1, MMP7, MMP8, and MMP13, were also decreased by PACAP addition upon oxidative and mechanical stress, while the activity of MMP9 seemed not to be influenced by the neuropeptide. These results suggest that application of PACAP can help to preserve the integrity of the newly synthetized cartilage matrix via signaling mechanisms, which ultimately inhibit the activity of matrix destroying enzymes under cellular stress. It implies the prospect that application of PACAP can ameliorate articular cartilage destruction in joint diseases.

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Section: Discussionsupporting

confidence: 72%

Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) Reduces Oxidative and Mechanical Stress-Evoked Matrix Degradation in Chondrifying Cell Cultures

Szentléleky

Szegeczki

Karanyicz

et al. 2019

IJMS

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“…The camera used was DP71 (Olympus). Like in previous reports, the number of positive cells in each group was calculated as described below, and the differences subjected to statistical analysis [ 33 ]. The number of positively stained cells was counted in articular cartilage.…”

Section: Methodsmentioning

confidence: 99%

Intraarticularly-Injected Mesenchymal Stem Cells Stimulate Anti-Inflammatory Molecules and Inhibit Pain Related Protein and Chondrolytic Enzymes in a Monoiodoacetate-Induced Rat Arthritis Model

Ichiseki

Shimazaki

Ueda

et al. 2018

IJMS

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Persistent inflammation is well known to promote the progression of arthropathy. mesenchymal stem cells (MSCs) have been shown to possess anti-inflammatory properties and tissue differentiation potency. Although the experience so far with the intraarticular administration of mesenchymal stem cell (MSC) to induce cartilage regeneration has been disappointing, MSC implantation is now being attempted using various surgical techniques. Meanwhile, prevention of osteoarthritis (OA) progression and pain control remain important components of the treatment of early-stage OA. We prepared a shoulder arthritis model by injecting monoiodoacetate (MIA) into a rat shoulder, and then investigated the intraarticular administration of MSC from the aspects of the cartilage protective effect associated with their anti-inflammatory property and inhibitory effect on central sensitization of pain. When MIA was administered in this rat shoulder arthritis model, anti-Calcitonin Gene Related Peptide (CGRP) was expressed in the joint and C5 spinal dorsal horn. Moreover, expression of A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5), a marker of joint cartilage injury, was similarly elevated following MIA administration. When MSC were injected intraarticularly after MIA, the expression of CGRP in the spinal dorsal horn was significantly deceased, indicating suppression of the central sensitization of pain. The expression of ADAMTS 5 in joint cartilage was also significantly inhibited by MSC administration. In contrast, a significant increase in the expression of TNF-α stimulated gene/protein 6 (TSG-6), an anti-inflammatory and cartilage protective factor shown to be produced and secreted by MSC intraarticularly, was found to extend to the cartilage tissue following MSC administration. In this way, the intraarticular injection of MSC inhibited the central sensitization of pain and increased the expression of the anti-inflammatory and cartilage protective factor TSG-6. As the least invasive conservative strategies possible are desirable in the actual clinical setting, the intraarticular administration of MSC, which appears to be effective for the treatment of pain and cartilage protection in early-stage arthritis, may achieve these aims.

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“…HYAL1 is primarily an intracellular, low pH, lysosomal hyaluronidase. Recent studies using a conditional (Col2a-Cre) Hyal2 −/− reported increases in HA within the PCM, increased overall HA and increased HA size [46]. HYAL2 is considered a cell surface [47], endosomal [48] and lysosomal hyaluronidase [49,50].…”

Section: Ha Turnover Within the Pcmmentioning

confidence: 99%

“…HYAL2 is considered a cell surface [47], endosomal [48] and lysosomal hyaluronidase [49,50]. In fact, many of the hyaluronidases and receptors that have been considered as critical participants in HA turnover including: HYAL1, HYAL2, HYAL3 [46,[51][52][53][54], CD44 [23,24,[55][56][57], PH-20 [58], KIAA [59] and TMEM2 [60] all are associated with the chondrocytes and PCM. Lastly, Fosang et al using confocal microscopy, observed the accumulation of intracellular G1-ITEGE in situ within cartilage chondrocytes of porcine articular cartilage [61].…”

Section: Ha Turnover Within the Pcmmentioning

confidence: 99%

The pericellular hyaluronan of articular chondrocytes

et al. 2019

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The story of hyaluronan in articular cartilage, pericellular hyaluronan in particular, essentially is also the story of aggrecan. Without properly tethered aggrecan, the load bearing function of cartilage is compromised. The anchorage of aggrecan to the cell surface only occurs due to the binding of aggrecan to hyaluronan-with hyaluronan tethered either to a hyaluronan synthase or by multivalent binding to CD44. In this review, details of hyaluronan synthesis are discussed including how HAS2 production of hyaluronan is necessary for normal chondrocyte development and matrix assembly, how an abundance or deficit of pericellular hyaluronan alters chondrocyte metabolism, and whether hyaluronan size matters or changes with aging or disease. The biomechanical role and matrix assembly function of hyaluronan in addition to the functions of hyaluronidases are discussed. The turnover of hyaluronan is considered including mechanisms by which its turnover, at least in part, is mediated by endocytosis by chondrocytes and regulated by aggrecan degradation. Differences between turnover and clearance of newly synthesized hyaluronan and aggrecan versus the half-life of hyaluronan remaining within the inter-territorial matrix of cartilage are discussed. The release of neutral pH-acting hyaluronidase activity remains one unanswered question concerning the loss of cartilage hyaluronan in osteoarthritis. Signaling events driven by changes in hyaluronan-chondrocyte interactions may involve a chaperone function of CD44 with other receptors/cofactors as well as the changes in hyaluronan production functioning as a metabolic rheostat.

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Conditional knockdown of hyaluronidase 2 in articular cartilage stimulates osteoarthritic progression in a mice model

Cited by 13 publications

References 42 publications

Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) Reduces Oxidative and Mechanical Stress-Evoked Matrix Degradation in Chondrifying Cell Cultures

Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) Reduces Oxidative and Mechanical Stress-Evoked Matrix Degradation in Chondrifying Cell Cultures

Intraarticularly-Injected Mesenchymal Stem Cells Stimulate Anti-Inflammatory Molecules and Inhibit Pain Related Protein and Chondrolytic Enzymes in a Monoiodoacetate-Induced Rat Arthritis Model

The pericellular hyaluronan of articular chondrocytes

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