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Osteoarthritis — an untreatable disease?

Key Points

  • Osteoarthritis (OA) is a painful, complex disease that affects millions of people worldwide. There is currently no disease-modifying therapy for OA, and existing drugs to treat symptoms of OA are largely ineffective. The lack of a validated animal model and the multifactorial nature of the disease make the discovery and development of new drugs even more challenging.

  • OA is a disease of the whole joint that involves many pathophysiological processes that arise from a dysregulation in the function of cytokines and growth factors, prostaglandins, cartilage matrix fragments, neuropeptides, reactive oxygen intermediates, proteolytic enzymes and protease inhibitors. Dysregulation of these factors sets in motion a cycle of degeneration of cartilage, bone, ligaments and synovium that coincides with an inflammatory response and peripheral and central nervous system sensitization.

  • Current treatments for OA include acetaminophen, non-steroidal anti-inflammatories, cyclooxygenase 2 (COX2) inhibitors, and intra-articular hyaluronic acid or steroid injections. However, disease-modifying efficacy has not been demonstrated for any of these drugs. These drugs are only moderately effective, leaving the patients with a substantial pain burden and often gastrointestinal side effects after chronic administration.

  • Disease-modifying drugs currently in various stages of clinical development include inhibitors against matrix metalloproteinases, interleukin-1β-convertase (ICE) and cathepsin K, and the nutraceutical glucosamine. Inhibitors against lipoxygenase and COX2, as well as nitric oxide analgesics and novel NSAIDS, are being tested in the clinic for the symptomatic treatment of OA.

  • The complex pathology of OA calls for a systems biology approach to dissecting the molecular pathways of disease initiation and progression, and to this end much effort is now focused on identifying and validating biomarkers and disease models for OA.

Abstract

Osteoarthritis is a painful and disabling disease that affects millions of patients. Its aetiology is largely unknown, but is most likely multi-factorial. Osteoarthritis poses a dilemma: it often begins attacking different joint tissues long before middle age, but cannot be diagnosed until it becomes symptomatic decades later, at which point structural alterations are already quite advanced. In this review, osteoarthritis is considered as a disease of the whole joint that may result from multiple pathophysiological mechanisms, one of which is the dysregulation of lipid homeostasis. No proven disease-modifying therapy exists for osteoarthritis and current treatment options for chronic osteoarthritic pain are insufficient, but new pharmacotherapeutic options are emerging.

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Figure 1: Common target sites for osteoarthritis.
Figure 2: Articular structures that are affected in osteoarthritis.
Figure 3: Current osteoarthritis treatment options.
Figure 4: Vicious cycle of osteoarthritis.
Figure 5: Targets for the development of disease- (a) or symptom-modifying (b) drugs for osteoarthritis.

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Acknowledgements

We wish to thank J. Pietsch and B. Schölkens for their valuable input to the preparation of this review.

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Correspondence to Heike A. Wieland.

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Competing interests

The authors are employees of Aventis Pharma Deutschland GmbH, a company of the Sanofi-Aventis group which is developing drugs that target osteoarthritis.

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DATABASES

Entrez Gene

ADAMTS1

ADAMTS4

ADAMTS5

bFGF

COMP

ICE

IGF1

IL-1β

MMP1

MMP3

MMP8

MMP13

NF-κB

PPARγ

TGFβ

OMIM

Osteoarthritis

Paget's disease

rheumatoid arthritis

Wilson's disease

FURTHER INFORMATION

National Institutes of Health (NIH)-sponsored Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT)

Glossary

SYNOVITIS

Inflammation of the synovium, the tissue that produces joint-lubricating fluid.

LEPTIN

A polypeptide hormone ligand related to the family of interleukin-6 cytokines encoded by the obese (ob) gene and secreted by adipocytes.

ENDOCHONDRAL OSSIFICATION

A type of bone formation that occurs by replacement of hyaline cartilage.

EBURNATION

Spikes of granulation and fibrous tissue reach the joint surface. The tissue undergoes endochondral ossification and penetrates the thinning cartilage, eventually exposing smooth, dense bone on the articular surface.

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Wieland, H., Michaelis, M., Kirschbaum, B. et al. Osteoarthritis — an untreatable disease?. Nat Rev Drug Discov 4, 331–344 (2005). https://doi.org/10.1038/nrd1693

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