Pathobiology of Osteoarthritis: Pathomechanisms and Potential Therapeutic Targets

Roach, Helmtrud I.; Aigner, Thomas; Söder, S.; Haag, Jill D.; Welkerling, Heike

doi:10.2174/138945007779940160

Cited by 76 publications

(52 citation statements)

References 109 publications

(134 reference statements)

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“…The majority of chondrocytes in OA cartilage, however, are severely degenerated (15) and many are undergoing cell death or "chondroptosis" (16). It was recently demonstrated that OA cartilage is associated with a reduction and loss of regulators of the autophagy pathway (ULK, Beclin-1, and LC3 expression) and an increase in cell death (characterized by increased expression of PARP p85) (14).…”

Section: Discussionmentioning

confidence: 99%

Uric acid is a danger signal of increasing risk for osteoarthritis through inflammasome activation

Denoble¹,

Huffman²,

Stäbler³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

237

178

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Uric acid (UA) is known to activate the NLRP3 (Nacht, leucine-rich repeat and pyrin domain containing protein 3) inflammasome. When activated, the NLRP3 (also known as NALP3) inflammasome leads to the production of IL-18 and IL-1β. In this cohort of subjects with knee osteoarthritis (OA), synovial fluid uric acid was strongly correlated with synovial fluid IL-18 and IL-1β. Synovial fluid uric acid and IL-18 were strongly and positively associated with OA severity as measured by both radiograph and bone scintigraphy, and synovial fluid IL-1β was associated with OA severity but only by radiograph. Furthermore, synovial fluid IL-18 was associated with a 3-y change in OA severity, on the basis of the radiograph. We conclude that synovial fluid uric acid is a marker of knee OA severity. The correlation of synovial fluid uric acid with the two cytokines (IL-18 and IL-1β) known to be produced by uric acidactivated inflammasomes and the association of synovial fluid IL-18 with OA progression, lend strong support to the potential involvement of the innate immune system in OA pathology and OA progression.arthritis | inflammation | interleukin-18 | interleukin-1β | tumor necrosis factor alpha U ric acid (UA) is constitutively present in normal cells, increased in concentration when cells are injured, and released from dying cells (1). On the basis of a theory proposed by Matzinger, the products of cell stress and tissue damage may represent "danger signals" that function as endogenous adjuvants recognized by the immune system (2). Matzinger proposed that immunity is controlled by an internal conversation between tissues and the cells of the immune system (3). This proposal introduced a new immunological model of an immune system capable of sensing cellular stress and tissue damage (4). Shi subsequently identified uric acid as one of these principal endogenous danger signals released from injured cells and mediating the immune response to antigens associated with injured cells (1). The molecular mechanism of this innate immune response to uric acid was further shown to be the result of the activation of the NALP3 inflammasome, a cytosolic, multiprotein complex that mediates caspase activation by uric acid crystals, leading to the production of the active forms of IL-1β and IL-18 (5). Recently, Kono et al. demonstrated in an in vivo hepatoxicity mouse model that uric acid is a physiological regulator of the inflammation induced by tissue injury (6). These data form the basis for our hypothesis that synovial fluid uric acid is a factor regulating tissue inflammation, disease severity, and progression in osteoarthritis (OA).Uric acid is best known for its role in gout. When uric acid concentrations exceed the limit of solubility (∼6.8 mg/dL or even lower under conditions of low pH or temperature), crystal formation can ensue, which is capable of activating the NALP3 inflammasome (5) and triggering the acute severe attacks of joint inflammation characteristic of gout (7). Several studies have previously posited an association o...

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Section: Discussionmentioning

confidence: 99%

Uric acid is a danger signal of increasing risk for osteoarthritis through inflammasome activation

Denoble¹,

Huffman²,

Stäbler³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

237

178

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“…O steoarthritis (OA) 3 is the most common disorder affecting diarthrodial joints and has been associated with agerelated loss of homeostatic balance between degeneration and repair mechanisms. OA is often a consequence of abnormal mechanical forces that lead to altered metabolism in chondrocytes, the single cellular component in articular cartilage.…”

mentioning

confidence: 99%

“…OA is often a consequence of abnormal mechanical forces that lead to altered metabolism in chondrocytes, the single cellular component in articular cartilage. Although OA is generally classified as a noninflammatory disease, prominent proinflammatory mediators, including cytokines, PGs, and reactive oxygen species are believed to play pivotal roles in the disease pathogenesis (1)(2)(3)(4)(5)(6). It is increasingly appreciated that chondrocytes, like osteocytes in bone, function as mechanosensors by which local mechanical forces influence cellular metabolism.…”

mentioning

confidence: 99%

Prostaglandin E2 Exerts Catabolic Effects in Osteoarthritis Cartilage: Evidence for Signaling via the EP4 Receptor

Attur

Al-Mussawir

Patel

et al. 2008

The Journal of Immunology

179

132

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Elevated levels of PGE2 have been reported in synovial fluid and cartilage from patients with osteoarthritis (OA). However, the functions of PGE2 in cartilage metabolism have not previously been studied in detail. To do so, we cultured cartilage explants, obtained from patients undergoing knee replacement surgery for advanced OA, with PGE2 (0.1–10 μM). PGE2 inhibited proteoglycan synthesis in a dose-dependent manner (maximum 25% inhibition (p < 0.01)). PGE2 also induced collagen degradation, in a manner inhibitable by the matrix metalloproteinase (MMP) inhibitor ilomastat. PGE2 inhibited spontaneous MMP-1, but augmented MMP-13 secretion by OA cartilage explant cultures. PCR analysis of OA chondrocytes treated with PGE2 with or without IL-1 revealed that IL-1-induced MMP-13 expression was augmented by PGE2 and significantly inhibited by the cycolooygenase 2 selective inhibitor celecoxib. Conversely, MMP-1 expression was inhibited by PGE2, while celecoxib enhanced both spontaneous and IL-1-induced expression. IL-1 induction of aggrecanase 5 (ADAMTS-5), but not ADAMTS-4, was also enhanced by PGE2 (10 μM) and reversed by celecoxib (2 μM). Quantitative PCR screening of nondiseased and end-stage human knee OA articular cartilage specimens revealed that the PGE2 receptor EP4 was up-regulated in OA cartilage. Moreover, blocking the EP4 receptor (EP4 antagonist, AH23848) mimicked celecoxib by inhibiting MMP-13, ADAMST-5 expression, and proteoglycan degradation. These results suggest that PGE2 inhibits proteoglycan synthesis and stimulates matrix degradation in OA chondrocytes via the EP4 receptor. Targeting EP4, rather than cyclooxygenase 2, could represent a future strategy for OA disease modification.

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“…However, generally speaking, damage is repaired by chondrocytes in the subchondral bone plate or mesenchymal stem cells, inflammatory cells and cytokines in the bone marrow. Ultimately, damage is repaired by fibrous cartilage (Roach et al, 2007;Richter, 2009). From the histological staining results in the control group, we observed that the defects were filled with fibrous cartilage (Figs.…”

Section: Discussionmentioning

confidence: 89%

Repair of articular cartilage defects in rabbits through tissue-engineered cartilage constructed with chitosan hydrogel and chondrocytes

Zhao

Chen

Liu

et al. 2015

J. Zhejiang Univ. Sci. B

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Abstract:Objective: In our previous work, we prepared a type of chitosan hydrogel with excellent biocompatibility. In this study, tissue-engineered cartilage constructed with this chitosan hydrogel and costal chondrocytes was used to repair the articular cartilage defects. Methods: Chitosan hydrogels were prepared with a crosslinker formed by combining 1,6-diisocyanatohexane and polyethylene glycol. Chitosan hydrogel scaffold was seeded with rabbit chondrocytes that had been cultured for one week in vitro to form the preliminary tissue-engineered cartilage. This preliminary tissue-engineered cartilage was then transplanted into the defective rabbit articular cartilage. There were three treatment groups: the experimental group received preliminary tissue-engineered cartilage; the blank group received pure chitosan hydrogels; and, the control group had received no implantation. The knee joints were harvested at predetermined time. The repaired cartilage was analyzed through gross morphology, histologically and immunohistochemically. The repairs were scored according to the international cartilage repair society (ICRS) standard. Results: The gross morphology results suggested that the defects were repaired completely in the experimental group after twelve weeks. The regenerated tissue connected closely with subchondral bone and the boundary with normal tissue was fuzzy. The cartilage lacuna in the regenerated tissue was similar to normal cartilage lacuna. The results of ICRS gross and histological grading showed that there were significant differences among the three groups (P<0.05). Conclusions: Chondrocytes implanted in the scaffold can adhere, proliferate, and secrete extracellular matrix. The novel tissue-engineered cartilage constructed in our research can completely repair the structure of damaged articular cartilage.

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Pathobiology of Osteoarthritis: Pathomechanisms and Potential Therapeutic Targets

Cited by 76 publications

References 109 publications

Uric acid is a danger signal of increasing risk for osteoarthritis through inflammasome activation

Uric acid is a danger signal of increasing risk for osteoarthritis through inflammasome activation

Prostaglandin E2 Exerts Catabolic Effects in Osteoarthritis Cartilage: Evidence for Signaling via the EP4 Receptor

Repair of articular cartilage defects in rabbits through tissue-engineered cartilage constructed with chitosan hydrogel and chondrocytes

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