The pathogenesis of osteoarthritis

Howell, David S.; Sapolsky, Asher I.; Pita, Julio C.; Woessner, Jeff

doi:10.1016/0049-0172(76)90015-9

Cited by 75 publications

(29 citation statements)

References 56 publications

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“…Acid and neutral proteases have been implicated as Possible causative agents in OA (12,18,19). Although pentosan polysulfate did not significantly alter tHe course of development of knee joint pathology in our studies, it is possible that the dose we selected is too high and that anionic polyelectrolytes of this type should be used in very low concentrations (Halse J: personal communication).…”

Section: Discussionmentioning

confidence: 81%

A new model of osteoarthritis in rabbits

Butler¹,

Colombo²,

Hickman³

et al. 1983

Arthritis & Rheumatism

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A battery of steroidal and nonsteroidal antirheumatic drugs and protease inhibitors were tested by intraarticular injection for effects on osteoarthritis of the knees of rabbits subjected to partial lateral meniscectomy and section of the sesamoid and collateral fibular ligaments. Among the standard drugs, only the glucocorticoid, triamcinolone hexacetonide, and the protease inhibitor, tranexamic acid, exhibited significant anti-osteoarthritic activity. An experimental drug, GPA 2163, also offered some protection against joint degeneration. The nonsteroidal antiinflammatory drugs had no effect on the development of osteoarthritis in the model.In a previous report from this laboratory, a new surgical method for experimental induction of osteoarthritis (OA) in rabbits was described (1). This method, which involves partial lateral meniscectomy and section of the sesamoid and collateral ligaments, induces a relatively consistent and reproducible degenerative disease of rabbit knees in a period of 6 weeks. A battery of selected steroidal drugs, nonsteroidal antiinflammatory drugs (NSAIDs), and other drugs reputed to possess antirheumatic properties or otherwise influence connective tissues have subsequently been tested for systemic efficacy in retarding or reversing the cartilage deterioration in knees of rabbits subjected to the new procedure (2). A few drugs exerted marked to moderate anti-OA activity. These included the steroids, paramethasone and triamcinolone, only 2 of 11 NSAlDs tested (pirprofen and the experimental drug, CGS 5391B), the glucofuranoside derivative, tribenoside, and the anti-estrogen, tamoxifen. The anti-osteoarthritic activity could not be explained in terms of known antiinflammatory or other properties of these drugs.In the present study, additional selected drugs have been tested for possible anti-OA efficacy by direct intraarticular (IA) injection in laterally meniscectomized rabbits. MATERIALS AND METHODSMale New Zealand white rabbits (Hare Farms) weighing approximately 4 kg each were subjected to partial lateral meniscectomy with section of the fibular collateral and sesamoid ligaments or sham operation, as previously described (1). The animals were maintained on a diet of standard rabbit pellets and tap water ad libitum.Intraarticular injections into the knee joint of test drugs or vehicle were given either as a single 0.0s ml dose 7 days post-surgery or as two 0.05 ml doses on days 7 and 14 post-surgery. The injections were made using 0.25-ml glass syringes and 26-gauge one-half-inch needles for soluble drugs or 23-gauge one-half-inch needles for suspensions. The source, dosage, and vehicle used for each test drug are shown in Table 1. One drug, triamcinolone hexacetonide, was also injected periarticularly (PA) in one group of rabbits (i.e., the compound was injected into the soft tissue immediately adjacent to the knee joint).In each rabbit tested, the right (operated) knee was injected with drug, while the left (unoperated) knee was injected with vehicle only, as a test for possible i...

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Section: Discussionmentioning

confidence: 81%

A new model of osteoarthritis in rabbits

Butler¹,

Colombo²,

Hickman³

et al. 1983

Arthritis & Rheumatism

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“…The neutral protease synthesized by chondrocytes is a metalloprotease with properties very similar to the metalloproteases of osteoarthritic human articular cartilage described by Sapolsky et a1 (14,17).…”

Section: Discussionmentioning

confidence: 98%

Induction of the synthesis of latent collagenase and latent neutral protease in chondrocytes by a factor synthesized by activated macrophages

Ridge¹,

Oronsky²,

Kerwar³

1980

Arthritis & Rheumatism

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The spent medium of stimulated peritoneal macrophages coqtains a factor or factors that induce the de novo synthesis of collagenase and neutral protease(s) in primary cultures of articular chondrocytes. The synthesis of this inducing factor by stimulated macrophages is inhibited by cycloheximide, indicating that the factor is a protein. The inducing factor is heat stable and stable to tryspin treatment, but it is partially inactivated on treatment to pH 2.0. The inducing factor is not retained 04 concanavalin Sepharose, is staple to reductive alkylation, and has an apparent molecular weight of a p proximately 30,OOO. Addition of the inducing factor to cartilage slices also results in the synthesis of both collagenase and neutral protease by the slices. Both of these enzymes synthesized by chondrocytes are in the latent form and are activated by either trypsin or plasmin. The neutral protease (MW 22,000) is a metalloprotease and is inhibited by o-phenanthroline and by D-penicillamine but not by phenylmethane sulfonylfluoride or iodoacetic acid. Induction of these latent en- Submitted for publication August 6, 1979; accepted in revised form December 26, 1979. zymes in chondrocytes occurs between 8 and 16 hours after exposure to the inducing factor and is completely blocked by cycloheximide. The spent medium of stimulated lymphocytes (concanavalin A) does not induce the synthesis of these enzymes in chondrocytes, suggesting that the synthesis of the inducing factor may be a prop erty specific to stimulated macrophages.Immunologic disturbances leading to the infiltration of mononuclear and polymorphonuclear cells into the synovium are a characteristic feature of inflammatory joint disease (1). It has been postulated that these cells contribute to the breakdown of articular collagen and proteoglycans that is observed in the disease. This destruction of the matrix can occur by at least two mechanisms. In one mechanism, intracellular neutral proteases and collagenase of the polymorphonuclear cells are released in the synovium and lead to the enzymatic degradation of the cartilage matrix ( 2 4 ) . A second mechanism involves the interaction between the various cell types in the synovium leading to the synthesis of collagenase. Dayer et a1 (5,6) have shown that products synthesized by stimulated lymphocytes can activate synovial cells to synthesize abnormal levels of collagenase. Products of stimulated lymphocytes can also interact with macrophages and result in the synthesis of collagenase by the latter cells (7).Cell-cell interactions between mononuclear cells and chondrocytes have not been investigated in detail. In a recent preliminary communication by Phadke et a1

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“…Cartilage injuries in athletes and the elderly can be seriously disabling and predispose to the development of osteoarthritis [16,2]. The poor local tissue response does little to reconstitute focal injury, and a combination of minimal vascular access, low cell to matrix ratio, and diminished growth factor ligand and receptor function, trigger only minimal repair.…”

Section: Introductionmentioning

confidence: 99%

Exogenous insulin‐like growth factor‐I stimulates an autoinductive IGF‐I autocrine/paracrine response in chondrocytes

Nixon

Saxer

Brower-Toland

2001

Journal Orthopaedic Research

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The modulation of insulin-like growth factor-I (IGF-I) gene expression by chondrocytes following exogenous IGF-I supplementation of culture was assessed to examine the hypothesis that constitutive IGF-I mRNA activity is suppressed by exogenous administration of IGF-I to cartilage in situ. Chondrocytes in monolayer culture were treated with 0, 10 or 100 ng/ml IGF-I for 48 h and resultant IGF-I and matrix gene expression patterns were assessed by quantitative polymerase chain reaction (qPCR) and northern blotting, respectively. Effective translation of proteoglycan (PG) as a response to IGF-I was determined by dimethylmethylene blue (DMMB) dye-binding assay. To determine the temporal nature of the IGF-I autocrine/paracrine response to exogenous IGF-I, chondrocyte cultures were treated with 100 nglml IGF-I and the IGF-I mRNA response was assessed at 0,4, 12,24,48 and 72 h. Significant increases in chondrocyte density and in PG synthesis occurred during treatment of chondrocyte cultures with 10 and 100 ng/ml IGF-I. Persistent exposure of chondrocytes to 100 ng/ml IGF-I resulted in maximal IGF-1 mRNA response at 24 h, with declining message accumulation at 48 and 72 h. These data suggest that IGF-I induces an autoinductive IGF-I autocrinel paracrine transcriptional response. The clinical ramifications of these findings include support for the use of exogenous IGF-I for cartilage repair where it could conceivably amplify and extend the effect of exogenous IGF-I beyond the transitory persistence of supplemental IGF-I ligand in repair constructs.

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The pathogenesis of osteoarthritis

Cited by 75 publications

References 56 publications

A new model of osteoarthritis in rabbits

A new model of osteoarthritis in rabbits

Induction of the synthesis of latent collagenase and latent neutral protease in chondrocytes by a factor synthesized by activated macrophages

Exogenous insulin‐like growth factor‐I stimulates an autoinductive IGF‐I autocrine/paracrine response in chondrocytes

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