Autocrine regulation of collagenase 3 (matrix metalloproteinase 13) during osteoarthritis

Hyaluronan exerts a variety of biological effects on cells including changes in cell migration, proliferation, and matrix metabolism. However, the signaling pathways associated with the action of hyaluronan on cells have not been clearly defined. In some cells, signaling is induced by the loss of cell-hyaluronan interactions. The goal of this study was to use hyaluronan oligosaccharides as a molecular tool to explore the effects of changes in cell-hyaluronan interactions and determine the underlying molecular events that become activated. In this study, hyaluronan oligosaccharides induced the loss of extracellular matrix proteoglycan and collagen from cultured slices of normal adult human articular cartilage. This loss was coincident with an increased expression of matrix metalloproteinase (MMP)-13. MMP-13 expression was also induced in articular chondrocytes by hyaluronan (HA) hexasaccharides but not by HA tetrasaccharides nor high molecular weight hyaluronan. MMP-13 promoterreporter constructs in CD44-null COS-7 cells revealed that both CD44-dependent and CD44-independent events mediate the induction of MMP-13 by hyaluronan oligosaccharides. Electromobility gel shift assays demonstrated the activation of chondrocyte NFB by hyaluronan oligosaccharides. NFB activation was also documented in C-28/I2 immortalized human chondrocytes by luciferase promoter assays and phosphorylation of IKK-␣/␤. The link between activation of NFB and MMP-13 induction by HA oligosaccharides was further confirmed through the use of the NFB inhibitor helenalin. Inhibition of MAP kinases also demonstrated the involvement of p38 MAP kinase in the hyaluronan oligosaccharide induction of MMP-13. Our findings suggest that hyaluronan-CD44 interactions affect matrix metabolism via activation of NFB and p38 MAP kinase.In many tissues cell-matrix interactions serve to regulate cellular homeostasis (1, 2). Interference with these associations typically signal cells to initiate matrix repair, cell proliferation, or even cell migration. Such interactions are especially important in tissues such as articular cartilage, a tissue rich in extracellular matrix but with limited vascular access for systemic control of homeostasis. Chondrocytes are thus highly dependent on cell-matrix interactions as a primary means to "sense" changes in the extracellular environment (3). Most investigations in this area focus on cell signaling induced through the interaction of integrin receptors with collagens, fibronectin, laminin, matrilins, etc.(3-7). However, cell-matrix interactions involving hyaluronan (HA), 2 once thought to be predominately structural in nature, are now beginning to receive increasing attention as initiators of cell signaling.HA is a high molecular weight polysaccharide consisting of repeating disaccharide units glucuronic acid and N-acetylglucosamine (8). In cartilage and many other connective tissues, HA serves as a central filamentous scaffold to which proteoglycans such as aggrecan and link protein become bound (9). This complex matrix networ...

show abstract

“…As a positive control, the C-28/I2 cells were treated with IL-1␤, conditions known to induce activation of MMP-13 (55). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Hyaluronan Oligosaccharides Induce Matrix Metalloproteinase 13 via Transcriptional Activation of NFκB and p38 MAP Kinase in Articular Chondrocytes

Ohno

Knudson

et al. 2006

Journal of Biological Chemistry

114

View full text Add to dashboard Cite

show abstract

“…Our analyses show individual differences that may be associated with the level of chondrocyte activity. Cyclical chondrocyte activation has been shown in chondrocytes from OA cartilage (34). Whether this applies to normal cartilage as well needs to be proven.…”

Section: Discussionmentioning

confidence: 98%

Matrix homeostasis in aging normal human ankle cartilage

Aurich¹,

Poole²,

Reiner³

et al. 2002

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. To study age-related (as opposed to arthritis-related) changes in collagen and proteoglycan turnover.Methods. Macroscopically nondegenerate normal ankle cartilage obtained from 30 donors (ages 16-75 years) was processed for in situ hybridization to detect messenger RNA (mRNA) of type IIB collagen (CIIB); antibodies to the C-propeptide of type II collagen (CPII), to the type II collagen (CII) collagenasegenerated cleavage neoepitope (Col2-3/4C short ), and to the CII denaturation product (Col2-3/4m) were used for immunohistochemistry analysis and immunoassay. In addition, immunoblotting was used to detect the 4 collagenases. Assays were also performed to detect glycosaminoglycan (GAG) content and the 846 epitope of aggrecan.Results. There were no significant changes in CII, GAG, and the content of the 846 epitope after the age of 30 years. Both mRNA for CIIB and the CPII were present in all zones, and CPII content did not change significantly with age. While the collagenase-cleaved CII showed a trend to increase with age, the denatured collagen did not. However, the molar ratio of cleaved versus denatured collagen was positively correlated with age. All 4 collagenases were detectable in the ankle cartilage but showed no identifiable changes in content with age.Conclusion. Synthesis and degradation of CII is associated with the pericellular matrix and is maintained at a steady state throughout life. The contents of CII and proteoglycan did not change. There was a significant reduction in the denaturation of CII with age, relative to collagenase-mediated cleavage. These observations reveal that, in aging of the intact ankle articular cartilage, there is no evidence of molecular degenerative changes of the kind observed in osteoarthritis, thereby distinguishing aging from the osteoarthritis process.The talar cartilages from the talocrural joint of the ankle offer opportunities for studying age-related changes in articular cartilage. We have shown that in a population of 470 adult organ donors (21-74 years of age), ϳ62% of the talar cartilages exhibited no macroscopic signs of degenerative changes often seen increasingly with age in other joints, such as the knee (1). Thus, samples from different donors can be studied with greater assurances that changes are associated with aging of the cartilage rather than with degenerative changes. Other advantages of using the ankle cartilages for studies of aging are that the talar cartilage is more uniform in thickness (1-2 mm [2]), representing a more consistent ratio of superficial to deep chondrocytes, and the talar cartilage is more uniform in stiffness (3,4).While degenerative changes and osteoarthritis (OA) do develop in the ankle (5), it is rare (6) compared with other joints, such as the knee. Our studies reveal that there are differences between the normal articular cartilages of the knee and ankle joints that may, in part, help to explain the differences in susceptibility to OA. Ankle cartilage is less responsive to catabolic stimulation by either fibronect...

show abstract

“…It is well described that elevated levels of pro-inflammatory cytokines provoke resident chondrocytes to initiate pathological expression and secretion of inflammatory mediators [18,32] and cartilagedegrading proteases [34,74]. In addition, excess stimulation of chondrocytes with proinflammatory cytokines such as TNF- and IL-1 induces apoptosis via activation of caspase-driven pathways [64,75].…”

Section: Discussionmentioning

confidence: 99%

Melanocortin peptides protect chondrocytes from mechanically induced cartilage injury

Kaneva

Kerrigan

Grieco

et al. 2014

Biochemical Pharmacology

View full text Add to dashboard Cite

Conclusion:Melanocortin peptide pre-treatment prevented chondrocyte death following mechanical impact to cartilage and led to a marked reduction of pro-inflammatory cytokines, whilst prompting the production of anti-inflammatory/pro-resolving cytokine IL-10.Development of small molecule agonists towards melanocortin receptors could thus be a viable approach for preventing chondrocyte inflammation and death within cartilage and represent an alternative approach for the treatment of osteoarthritis.

show abstract

Autocrine regulation of collagenase 3 (matrix metalloproteinase 13) during osteoarthritis

Cited by 110 publications

References 37 publications

Hyaluronan Oligosaccharides Induce Matrix Metalloproteinase 13 via Transcriptional Activation of NFκB and p38 MAP Kinase in Articular Chondrocytes

Hyaluronan Oligosaccharides Induce Matrix Metalloproteinase 13 via Transcriptional Activation of NFκB and p38 MAP Kinase in Articular Chondrocytes

Matrix homeostasis in aging normal human ankle cartilage

Melanocortin peptides protect chondrocytes from mechanically induced cartilage injury

Contact Info

Product

Resources

About