Scandinavian Journal of Rheumatology
ISSN: 0300-9742 (Print) 1502-7732 (Online) Journal homepage: http://www.tandfonline.com/loi/irhe20
Biochemical Aspects of Osteoarthritis D. S. Howell To cite this article: D. S. Howell (1990) Biochemical Aspects of Osteoarthritis, Scandinavian Journal of Rheumatology, 19:sup81, 5-7, DOI: 10.3109/03009749009096938 To link to this article: http://dx.doi.org/10.3109/03009749009096938
Published online: 12 Jul 2009.
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Article views: 3
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=irhe20 Download by: [Universität Osnabrueck]
Date: 16 March 2016, At: 18:35
Scand J Rheumatology (Suppl. 81): 5-7, 1990
Biochemical Aspects of Osteoarthritis D. S. HOWELL Arthritis Division, University of Miami, Florida, USA
Downloaded by [Universität Osnabrueck] at 18:35 16 March 2016
The development of new technologies in the fields of cellular and molecular biology is contributing significantly to the understanding of the disease processes involved in the development and progression of human osteoarthritis (OA). In particular the relationships between enzyme degradative pathways are becoming increasingly clear. Two prominent metalloenzymes and the specific tissue inhibitor of metalloproteinase have been studied in humans and animal models. Results indicate that such enzyme pathways may play a significant role in the degenerative tissue changes observed in OA.
D . S. Howell, Arthritis Division, University of Miami, P. 0. Box 016%0, Miami, Florida FL 33101, USA.
In the 1980s, a wealth of new technologies have been developed in the fields of cell biology and molecular biology, and these are having an increasing impact on the understanding and management of osteoarthritis (OA). Inter-relationships of enzyme degradative pathways, their activators and inhibitors, are becoming increasingly clear. In particular, it is becoming obvious that synovial cell message systems, initiated by low-grade inflammation, are involved in cartilage breakdown, and not simply amplifying synovial inflammation. Interleukin-1, tumour necrosis factor, prostaglandin E2 and interferon gamma from T-cells have been identified, not only in rheumatoid arthritis (RA), but also in osteoarthritic tissues. There is a likelihood of a strong deleterious effect on articular chondrocytes resultant from complex interactions leading to release and activation of proteases. This subject has recently been reviewed (1, 2). Our laboratory research group, in collaboration with that of the University of Montreal Arthritis Division, have studied the profile of two prominent metalloenzymes, and the specific tissue inhibitor of metalloproteinase (TIMP) in human O A patients. This was a continuation of long-term studies on such enzymes in humans and animal models (3). MATERIALS AND METHODS Osteoarthritic cartilage was analysed for neutral and acid metalloproteinase and TIMP. From thirty patients undergoing total knee replacement, 7 were selected for measurement of lateral compartment, and 6 were selected for measurement of medial compartment cartilage enzymes. Cartilage samples obtained from identical sites in 5 “normal” autopsy patients were used as controls. Clinical features, X-ray examination, carbon mapping and histologic criteria were assessed, and mild to moderate osteoarthritic disease was documented. Cartilage samples were extracted and analysed by newly modified methods, to avoid artefactual binding of TIMP to the enzymes during tissue preparation. RESULTS Lateral compartment
In our lateral compartment lesion studies we were specifically studying enzyme levels to see whether enzymes were elevated in the lesion tissue.
6
D.S. Howell
Scand J Rheumatology (Suppl. 81)
Downloaded by [Universität Osnabrueck] at 18:35 16 March 2016
Since the lateral compartment is spared heavy weight bearing forces, the possibility exists that atrophic cartilage lesions persisting or formed there might be distinguished from early OA lesions based on enzyme levels. In ongoing studies of atrophic cartilage in dogs, we have, in unpublished observations, found no elevation of neutral metalloproteinases in cartilage atrophy, in contrast to the findings in OA-like lesions of the Pond-Nuki dog model. In the current study, in lesions graded Mankin grade 5 f 2 , there was a disturbed enzyme profile. Significant elevation of acid latent and active metalloproteinase, together with some elevation of neutral metalloproteinase was shown. It was concluded that such lesions, regardless of the nature of their initiation, were at the time of study undergoing injury reactions consistent with OA, rather than the atrophy alone. Controlled cartilage analyses for remodelling and cell proliferation in young animals cartilage have failed to show elevated enzyme activity. Thus, the enzyme elevations were not considered to be the result of remodelling responses. Medial compartment Analyses of the medial compartment lesions showed highly significant elevations of both neutral and acid metalloproteinase. TIMP was quantitatively adequate to neutralise the total and latent metalloproteinases in the lateral compartment, but were insufficient to cover the total metalloproteinases in the medial compartment lesions, in which Mankin scales ranged 9-11. We conclude that the insufficiency of TIMP in the medial compartment may have a pathochemical role in rendering the matrix vulnerable to attack by activated metalloproteinases. We further conclude that the lateral compartment deserves further investigation as a probable site of early OA lesions in selected cases.
EFFECT OF A “CHONDROPROTECTIVE” AGENT IN AN ANIMAL MODEL O F OA Finally, we have studied the effects of prophylactic administration of a glycosaminoglycan complex, GP-C (Rumalon@)on the Moskowitz lapine model of osteoarthritis. Histologic grade, lesion size and neutral proteoglycan degrading enzyme activity at 6, 12, and 20 weeks post-surgery were studied. Significant protective action by this agent was shown in this animal model in respect of all parameters aforementioned (Figs. 1 and 2). It is concluded that Rumalon, and other agents we have studied in the past, are capable of modifying favourably the degradative tissue responses similar to those we have demonstrated above in the human studies.
REFERENCES 1. Krane SM, Amento EP, Goldring MB, et al. Cellular interaction and matrix destruction during
2. 3.
4. 5.
inflammatory processes within the joints. In: Kuettner KE, Schleyerbach R, Hascall VC, eds. Articular Cartilage Biochemistry. Raven Press, New York, 1986: 413-422. Pelletier J-P. Proceedings Symposium on Osteoarthritis - Proteases: Their involvement in OA. La Sapiniere, Val David PQ, Canada. J Rheumatol 1987; 14: 1-132. Dean D, Pelletier J-P, Martel-Pelletier J, Howell DS, Woessner JF. Profile of acid and neutral metalloproteinases in osteoarthritic (OA) and in control cartilages compared to specific tissue inhibitor of metalloproteinase (TIMP). Arthritis Rheum 1988; 31: Abstract no. 130. Suppl. S33. Howell DS, Carreno MR, Pelletier J-P, Muniz OE. Articular cartilage breakdown in a lapine model of osteoarthritis. Clin Orthop 1986; 213: 69-76. Moskowitz RW. Experimental models of degenerative joint disease. Semin Arthritis Rheum 1972; 2: 95-116.
Downloaded by [Universität Osnabrueck] at 18:35 16 March 2016
Scand J Rheumatology (Suppl. 81)
Biochemical aspects of OA
Fig. 1. 4 0 0 ~Safranin 0 and light green stain; medial femoral condylar cartilage, 20 weeks after partial medial meniscectomy. Fissures and brood capsules are seen. Indicator staining is weak for sulphated proteoglycans.
Fig. 2. 0.5 ml of Rumalon was injected intra-muscularly 3 times per week from 2nd to 20th week. No fissures nor brood capsules are seen. Staining for proteoglycans remains intense, showing satisfactory chondral protection under these conditions.
7
ISSN: 0300-9742 (Print) 1502-7732 (Online) Journal homepage: http://www.tandfonline.com/loi/irhe20
Biochemical Aspects of Osteoarthritis D. S. Howell To cite this article: D. S. Howell (1990) Biochemical Aspects of Osteoarthritis, Scandinavian Journal of Rheumatology, 19:sup81, 5-7, DOI: 10.3109/03009749009096938 To link to this article: http://dx.doi.org/10.3109/03009749009096938
Published online: 12 Jul 2009.
Submit your article to this journal
Article views: 3
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=irhe20 Download by: [Universität Osnabrueck]
Date: 16 March 2016, At: 18:35
Scand J Rheumatology (Suppl. 81): 5-7, 1990
Biochemical Aspects of Osteoarthritis D. S. HOWELL Arthritis Division, University of Miami, Florida, USA
Downloaded by [Universität Osnabrueck] at 18:35 16 March 2016
The development of new technologies in the fields of cellular and molecular biology is contributing significantly to the understanding of the disease processes involved in the development and progression of human osteoarthritis (OA). In particular the relationships between enzyme degradative pathways are becoming increasingly clear. Two prominent metalloenzymes and the specific tissue inhibitor of metalloproteinase have been studied in humans and animal models. Results indicate that such enzyme pathways may play a significant role in the degenerative tissue changes observed in OA.
D . S. Howell, Arthritis Division, University of Miami, P. 0. Box 016%0, Miami, Florida FL 33101, USA.
In the 1980s, a wealth of new technologies have been developed in the fields of cell biology and molecular biology, and these are having an increasing impact on the understanding and management of osteoarthritis (OA). Inter-relationships of enzyme degradative pathways, their activators and inhibitors, are becoming increasingly clear. In particular, it is becoming obvious that synovial cell message systems, initiated by low-grade inflammation, are involved in cartilage breakdown, and not simply amplifying synovial inflammation. Interleukin-1, tumour necrosis factor, prostaglandin E2 and interferon gamma from T-cells have been identified, not only in rheumatoid arthritis (RA), but also in osteoarthritic tissues. There is a likelihood of a strong deleterious effect on articular chondrocytes resultant from complex interactions leading to release and activation of proteases. This subject has recently been reviewed (1, 2). Our laboratory research group, in collaboration with that of the University of Montreal Arthritis Division, have studied the profile of two prominent metalloenzymes, and the specific tissue inhibitor of metalloproteinase (TIMP) in human O A patients. This was a continuation of long-term studies on such enzymes in humans and animal models (3). MATERIALS AND METHODS Osteoarthritic cartilage was analysed for neutral and acid metalloproteinase and TIMP. From thirty patients undergoing total knee replacement, 7 were selected for measurement of lateral compartment, and 6 were selected for measurement of medial compartment cartilage enzymes. Cartilage samples obtained from identical sites in 5 “normal” autopsy patients were used as controls. Clinical features, X-ray examination, carbon mapping and histologic criteria were assessed, and mild to moderate osteoarthritic disease was documented. Cartilage samples were extracted and analysed by newly modified methods, to avoid artefactual binding of TIMP to the enzymes during tissue preparation. RESULTS Lateral compartment
In our lateral compartment lesion studies we were specifically studying enzyme levels to see whether enzymes were elevated in the lesion tissue.
6
D.S. Howell
Scand J Rheumatology (Suppl. 81)
Downloaded by [Universität Osnabrueck] at 18:35 16 March 2016
Since the lateral compartment is spared heavy weight bearing forces, the possibility exists that atrophic cartilage lesions persisting or formed there might be distinguished from early OA lesions based on enzyme levels. In ongoing studies of atrophic cartilage in dogs, we have, in unpublished observations, found no elevation of neutral metalloproteinases in cartilage atrophy, in contrast to the findings in OA-like lesions of the Pond-Nuki dog model. In the current study, in lesions graded Mankin grade 5 f 2 , there was a disturbed enzyme profile. Significant elevation of acid latent and active metalloproteinase, together with some elevation of neutral metalloproteinase was shown. It was concluded that such lesions, regardless of the nature of their initiation, were at the time of study undergoing injury reactions consistent with OA, rather than the atrophy alone. Controlled cartilage analyses for remodelling and cell proliferation in young animals cartilage have failed to show elevated enzyme activity. Thus, the enzyme elevations were not considered to be the result of remodelling responses. Medial compartment Analyses of the medial compartment lesions showed highly significant elevations of both neutral and acid metalloproteinase. TIMP was quantitatively adequate to neutralise the total and latent metalloproteinases in the lateral compartment, but were insufficient to cover the total metalloproteinases in the medial compartment lesions, in which Mankin scales ranged 9-11. We conclude that the insufficiency of TIMP in the medial compartment may have a pathochemical role in rendering the matrix vulnerable to attack by activated metalloproteinases. We further conclude that the lateral compartment deserves further investigation as a probable site of early OA lesions in selected cases.
EFFECT OF A “CHONDROPROTECTIVE” AGENT IN AN ANIMAL MODEL O F OA Finally, we have studied the effects of prophylactic administration of a glycosaminoglycan complex, GP-C (Rumalon@)on the Moskowitz lapine model of osteoarthritis. Histologic grade, lesion size and neutral proteoglycan degrading enzyme activity at 6, 12, and 20 weeks post-surgery were studied. Significant protective action by this agent was shown in this animal model in respect of all parameters aforementioned (Figs. 1 and 2). It is concluded that Rumalon, and other agents we have studied in the past, are capable of modifying favourably the degradative tissue responses similar to those we have demonstrated above in the human studies.
REFERENCES 1. Krane SM, Amento EP, Goldring MB, et al. Cellular interaction and matrix destruction during
2. 3.
4. 5.
inflammatory processes within the joints. In: Kuettner KE, Schleyerbach R, Hascall VC, eds. Articular Cartilage Biochemistry. Raven Press, New York, 1986: 413-422. Pelletier J-P. Proceedings Symposium on Osteoarthritis - Proteases: Their involvement in OA. La Sapiniere, Val David PQ, Canada. J Rheumatol 1987; 14: 1-132. Dean D, Pelletier J-P, Martel-Pelletier J, Howell DS, Woessner JF. Profile of acid and neutral metalloproteinases in osteoarthritic (OA) and in control cartilages compared to specific tissue inhibitor of metalloproteinase (TIMP). Arthritis Rheum 1988; 31: Abstract no. 130. Suppl. S33. Howell DS, Carreno MR, Pelletier J-P, Muniz OE. Articular cartilage breakdown in a lapine model of osteoarthritis. Clin Orthop 1986; 213: 69-76. Moskowitz RW. Experimental models of degenerative joint disease. Semin Arthritis Rheum 1972; 2: 95-116.
Downloaded by [Universität Osnabrueck] at 18:35 16 March 2016
Scand J Rheumatology (Suppl. 81)
Biochemical aspects of OA
Fig. 1. 4 0 0 ~Safranin 0 and light green stain; medial femoral condylar cartilage, 20 weeks after partial medial meniscectomy. Fissures and brood capsules are seen. Indicator staining is weak for sulphated proteoglycans.
Fig. 2. 0.5 ml of Rumalon was injected intra-muscularly 3 times per week from 2nd to 20th week. No fissures nor brood capsules are seen. Staining for proteoglycans remains intense, showing satisfactory chondral protection under these conditions.
7
