Doxycycline disrupts chondrocyte differentiation and inhibits cartilage matrix degradation

Cole, Ada A.; Chubinskaya, Susan; Luchene, Lawrence J.; Chlebek, K.; Orth, Michael; Greenwald, Robert A.; Kuettner, Klaus E.; Schmid, Thomas

doi:10.1002/art.1780371204

Cited by 44 publications

(20 citation statements)

References 39 publications

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“…These experiments also demonstrated that the IC 50 levels for tetracyclines to inhibit NOS activity augmented by IL-1␤ were similar to the spontaneous release of NO. The concentrations of doxycycline that inhibited NO production in our studies are comparable to those required for the inhibition of matrix metalloproteases (19,(30)(31)(32)(33). In those studies, doxycycline at 20-50 g͞ml inhibited the activity of proteolytic enzymes such as collagenase and gelatinase, blocked proteoglycan degradation, reduced the cell death associated with proteoglycan loss, and augmented cartilage growth (31).…”

Section: Resultssupporting

confidence: 60%

A novel mechanism of action of tetracyclines: Effects on nitric oxide synthases

Amin

Attur

Thakker

et al. 1996

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

446

246

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Tetracyclines have recently been shown to have ''chondroprotective'' effects in inf lammatory arthritides in animal models. Since nitric oxide (NO) is spontaneously released from human cartilage affected by osteoarthritis (OA) or rheumatoid arthritis in quantities sufficient to cause cartilage damage, we evaluated the effect of tetracyclines on the expression and function of human OA-affected nitric oxide synthase (OA-NOS) and rodent inducible NOS (iNOS). Among the tetracycline group of compounds, doxycycline > minocycline blocked and reversed both spontaneous and interleukin 1␤-induced OA-NOS activity in ex vivo conditions. Similarly, minocycline > doxycycline inhibited both lipopolysaccharide-and interferon-␥-stimulated iNOS in RAW 264.7 cells in vitro, as assessed by nitrite accumulation. Although both these enzyme isoforms could be inhibited by doxycycline and minocycline, their susceptibility to each of these drugs was distinct. Unlike acetylating agents or competitive inhibitors of L-arginine that directly inhibit the specific activity of NOS, doxycycline or minocycline has no significant effect on the specific activity of iNOS in cell-free extracts. The mechanism of action of these drugs on murine iNOS expression was found to be, at least in part, at the level of RNA expression and translation of the enzyme, which would account for the decreased iNOS protein and activity of the enzyme. Tetracyclines had no significant effect on the levels of mRNA for ␤-actin and glyceraldehyde-3-phosphate dehydrogenase nor on levels of protein of ␤-actin and cyclooxygenase 2 expression. These studies indicate that a novel mechanism of action of tetracyclines is to inhibit the expression of NOS. Since the overproduction of NO has been implicated in the pathogenesis of arthritis, as well as other inf lammatory diseases, these observations suggest that tetracyclines should be evaluated as potential therapeutic modulators of NO for various pathological conditions.

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Section: Resultssupporting

confidence: 60%

A novel mechanism of action of tetracyclines: Effects on nitric oxide synthases

Amin

Attur

Thakker

et al. 1996

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

446

246

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“…In vitro, 10 M and 30 M doxycycline inhibited cartilage gelatinase activity by 44% and 82%, respectively (1). Degradation of embryonic avian tibias was inhibited by exposure in vitro to a similarly low concentration of the drug, following which collagenase and 62-kd gelatinase were no longer detectable in the spent culture medium (35).…”

Section: Discussionmentioning

confidence: 99%

Effects of doxycycline on progression of osteoarthritis: Results of a randomized, placebo‐controlled, double‐blind trial

Brandt¹,

Mazzuca²,

Katz³

et al. 2005

Arthritis & Rheumatism

248

198

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Objective. To confirm preclinical data suggesting that doxycycline can slow the progression of osteoarthritis (OA). The primary outcome measure was joint space narrowing (JSN) in the medial tibiofemoral compartment.Methods. In this placebo-controlled trial, obese women (n ‫؍‬ 431) ages 45-64 years with unilateral radiographic knee OA were randomly assigned to receive 30 months of treatment with 100 mg doxycycline or placebo twice a day. Tibiofemoral JSN was measured manually in fluoroscopically standardized radiographic examinations performed at baseline, 16 months, and 30 months. Severity of joint pain was recorded at 6-month intervals.Results. Seventy-one percent of all randomized subjects completed the trial. Radiographs were obtained from 85% of all randomized subjects at 30 months. Adherence to the dosing regimen was 91.8% among subjects who completed the study per protocol. After 16 months of treatment, the mean ؎ SD loss of joint space width in the index knee in the doxycycline group was 40% less than that in the placebo group (0.15 ؎ 0.42 mm versus 0.24 ؎ 0.54 mm); after 30 months, it was 33% less (0.30 ؎ 0.60 mm versus 0.45 ؎ 0.70 mm). Doxycycline did not reduce the mean severity of joint pain, although pain scores in both treatment groups were low at baseline and remained low throughout the trial, suggesting the presence of a floor effect. However, the frequency of followup visits at which the subject reported a >20% increase in pain in the index knee, relative to the previous visit, was reduced among those receiving doxycycline. In contrast, doxycycline did not have an effect on either JSN or pain in the contralateral knee. In both treatment groups, subjects who reported a >20% increase in knee pain at the majority of their followup visits had more rapid JSN than those whose pain did not increase.Conclusion. Doxycycline slowed the rate of JSN in knees with established OA. Its lack of effect on JSN in the contralateral knee suggests that pathogenetic mechanisms in that joint were different from those in the index knee.In the present report, we describe the results of a randomized, placebo-controlled, double-blind trial of the tetracycline antibiotic, doxycycline, in subjects with knee osteoarthritis (OA). Selection of doxycycline as a potential disease-modifying OA drug was based not on the premise that OA is an infectious disease, but rather on results of in vitro studies showing 1) that doxycycline inhibited the degradation of type XI collagen, one of the minor collagens of articular cartilage, by 72-kd gelati-

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“…MMP-8 is predominantly expressed by neutrophils, a cell type not present in our culture system. However, low levels of MMP-8 have been demonstrated to be produced by chondrocytes [Cole et al, 1994] and its potential presence in cartilage should not be discounted.…”

Section: Discussionmentioning

confidence: 99%

Retinoic acid combines with interleukin-1 to promote the degradation of collagen from bovine nasal cartilage: Matrix metalloproteinases-1 and -13 are involved in cartilage collagen breakdown

et al. 2000

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Retinoic acid (RetA) and interleukin-1alpha (IL-1) together can induce a reproducible release of proteoglycan fragments from bovine nasal cartilage in culture. However, release of collagen fragments with either agent alone is often variable. In this study over 70% of the total collagen was released from bovine nasal cartilage in culture by day 14 when RetA and IL-1 were combined. This release was accompanied by the appearance of collagenolytic activity in the culture medium that cleaved collagen specifically at the (1/4)/(3/4) position. Tissue inhibitor of metalloproteinases (TIMP) activity was present at day 7 but low or absent in media from resorbing tissue at day 14. The breakdown of cartilage collagen could be prevented by the addition of BB-94, a specific metalloproteinase inhibitor. These results suggest that RetA promotes the early release of TIMP from the tissue and that IL-1 stimulates pro-collagenase secretion which, when activated, exceeds the local concentration of TIMP. Thus in the later stages of culture collagen destruction occurs. Both MMP-1 and MMP-13 were detected and appear to be involved in IL-1 + RetA induced bovine cartilage destruction. However, for the first time, we also present evidence to suggest that MMP-13 is the predominant collagenase in this system.

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Doxycycline disrupts chondrocyte differentiation and inhibits cartilage matrix degradation

Cited by 44 publications

References 39 publications

A novel mechanism of action of tetracyclines: Effects on nitric oxide synthases

A novel mechanism of action of tetracyclines: Effects on nitric oxide synthases

Effects of doxycycline on progression of osteoarthritis: Results of a randomized, placebo‐controlled, double‐blind trial

Retinoic acid combines with interleukin-1 to promote the degradation of collagen from bovine nasal cartilage: Matrix metalloproteinases-1 and -13 are involved in cartilage collagen breakdown

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