Differential recovery of glycosaminoglycan after IL-1-induced degradation of bovine articular cartilage depends on degree of degradation

Abstract

Arthritic diseases are characterized by a progressive loss of extracellular matrix (ECM), which may ultimately lead to frank tissue loss and gross joint damage. The conditions under which chondrocytes can be induced to replenish or repair a depleted matrix (and thereby prevent or slow the disease process) remain unclear. If these conditions were known, then in principal one could design a therapeutic strategy that takes into account the capacity (or absence thereof) for chondrocytes to repair their matrix naturally.A number of model systems have provided some insights. For instance, IL-1-degraded cartilage tissues and cell suspensions are frequently employed as model systems to study cartilage metabolism under osteoarthritis-like conditions [1][2][3][4] and to assess the efficacy of various drug dGEMRIC = delayed gadolinium enhanced magnetic resonance imaging of cartilage; ECM = extracellular matrix; GAG = glycosaminoglycan; IL = interleukin; NMR = nuclear magnetic resonance. (Print ISSN 1478-6354; Online ISSN 1478-6362). This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any non-commercial purpose, provided this notice is preserved along with the article's original URL. AbstractIn the present study we examined cartilage matrix repair following IL-1-induced matrix depletion. Previous data indicated that, in some cases, chondrocytes can synthesize macromolecules to establish a functional extracellular matrix in response to a matrix-damaging insult or when placed in a threedimensional environment with inadequate matrix. However, the conditions under which such 'repair' can occur are not entirely clear. Prior studies have shown that chondrocytes in trypsindepleted young bovine articular cartilage can replenish tissue glycosaminoglycan (GAG) and that the rate of replenishment is relatively uniform throughout the tissue, suggesting that all chondrocytes have similar capacity for repair. In the present study we used the characteristic heterogeneous distribution of matrix depletion in response to IL-1 exposure in order to investigate whether the severity of depletion influenced the rate of GAG replenishment. We used the delayed GadoliniumEnhanced Magnetic Resonance Imaging of Cartilage (dGEMRIC) method to monitor the spatial and temporal evolution of tissue GAG concentration ([GAG]). For both mild (n = 4) and moderate (n = 10) IL-1-induced GAG depletion, we observed partial recovery of GAG (80% and 50% of baseline values, respectively) over a 3-week recovery period. During the first 2 weeks of recovery, [GAG] increased homogeneously at 10-15 mg/ml per week. However, during the third week the regions most severely depleted following IL-1 exposure showed negligible [GAG] accumulation, whereas those regions affected the least by IL-1 demonstrated the greatest accumulation. This finding could suggest that the most severely degraded regions do not recover fully, possibly because of more severe collagen damage; this possibility requires further examination.

Injury-related cell death and proteoglycan loss in articular cartilage: Numerical model combining necrosis, reactive oxygen species, and inflammatory cytokines

“…The result of possible partial recovery suggests that inhibition of cytokine activity or rapid cytokine clearance from the culture medium/joint space could suppress production of proteolytic enzymes and rescue PG synthesis via reduced cell death (see Eq (1) and Eq (S14) in S4 Text ). Similar PG recovery has been reported in experimental studies [ 74 , 75 ]. Specifically, our numerical model predicted PG recovery between days 10 and 30 ( Fig 8E , purple line) after removal of most IL-1 from the culture medium (day 10 in Fig 8A , purple line).…”

“…Specifically, our numerical model predicted PG recovery between days 10 and 30 ( Fig 8E , purple line) after removal of most IL-1 from the culture medium (day 10 in Fig 8A , purple line). During a similar time-window as shown by our model, previous in vitro experiments showed partial recovery of uninjured bovine cartilage GAG content over 3 weeks after changing the medium to that without IL-1 [ 75 ]. Interestingly, less recovery was observed in the most severely degraded regions compared to the more intact regions of the cartilage after IL-1 treatment.…”

MR Imaging of Articular Cartilage Physiology

“…Long-term In vitro studies have been conducted which enabled monitoring changes of GAG distribution over time with high resolution, allowing insight into the process of cartilage degradation, development, and repair (42). For example, in a study by Allen et al bovine cartilage plugs were monitored over time and showed chondrocytes could replenish GAG after trypsin depletion of GAG (118) and after interleukin-1 (IL-1) treatment (119). GAG measurements have been observed to correlate better in superficial layers of cartilage as compared with deep layers where MRI can overestimate GAG (120).…”

Analysis of cartilage matrix fixed charge density and three-dimensional morphology via contrast-enhanced microcomputed tomography

“…This regulation is the result of interactions between ionic interstitial fluid and negatively charged sulfated glycosaminoglycans (sGAGs) attached to the PG backbone (2). The amount and distribution of PGs changes substantially during development (3), during degeneration and repair (4,5), and in response to blunt trauma (6). Of particular clinical interest, initial stages of OA are marked by aggrecanasemediated cleavage of PGs (7), resulting in altered sulfation patterns (8) and progressive depletion of PGs from the ECM.…”