Editorial Overview
Musculoskeletal diseases: novel targets for therapeutic intervention

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Introduction

The term ‘musculoskeletal disease’ encompasses a huge variety of conditions involving many tissues and cell types. The first set of Musculoskeletal reviews in this issue of Current Opinion in Pharmacology detail disorders of the peripheral nerve and neuromuscular junction, the middle section deals with disorders involving both central and peripheral neurons and the final section concerns disorders of the joints and skeleton. The musculoskeletal system is complex, requiring coordinated interaction of neurological, muscular and skeletal elements to allow for controlled movement and support of the body. Pathological conditions ensue when there is disregulation of these interactions, degradation of the component tissues or disruption of normal cellular physiology within these tissues. This issue describes a variety of pathologies that result from molecular alterations of extracellular, cell surface and intracellular targets. Many of the molecular targets described are the focus of intense study within both the academic and industrial communities. It is anticipated that with a more detailed understanding of these molecules and the cellular interactions within the musculoskeletal system, novel therapeutics will be developed to treat these extremely debilitating diseases.

Section snippets

Disorders of the peripheral nerve and neuromuscular junction

The reviews begin with a consideration of therapies in peripheral neuropathies by Sutton and Winer (pp 291–295). Acute inflammatory demyelinating polyneuropathy, the commonest variant of Guillain–Barré syndrome (GBS), is the best studied peripheral neuropathy and the entity for which there are at least some therapies with published evidence of efficacy. The condition manifests with progressive symptoms of peripheral motor and sensory disturbance, which reach a plateau after some six to eight

Disorders of the motor system — amyotrophic lateral sclerosis

The next review (Morrison, pp 302–309) considers possible therapeutic approaches in the most common disorder of motor nerves in adults, amyotrophic lateral sclerosis (ALS). This dreaded disease, also termed Lou Gehrig's disease after the New York Yankees’ baseball player who died from ALS in 1941, is the most rapidly progressive of all the adult-onset neurodegenerative disorders, with an average survival from time of diagnosis of less than two years. There is no effective curative therapy or

Pain

Peripheral and central nervous system pathways of relevance to the musculoskeletal system are also discussed in the review on chronic pain by Priest and Hoggart (pp310–315). The dynamism of pain sensation is detailed, along with the adaptive mechanisms in the central nervous system that occur with the transition from acute to chronic pain. As discussed, the most effective therapeutic approaches at present for chronic pain involve multidisciplinary inputs, with regard for physical, social and

Skeletal Diseases

The second half of the Musculoskeletal section describes diseases and targets focused on the skeletal system. The three main diseases described in this section are rheumatoid arthritis, osteoarthritis and osteoporosis. The authors describe a variety of targets that are the focus of drug discovery efforts in a number of companies. Because of the mechanistic overlap among these diseases, many of these targets are under consideration for a number of different pathologies.

Rheumatoid arthritis

Rheumatoid arthritis is a systemic autoimmune inflammatory disease. This condition is primarily a disease that affects women of childbearing age and affects a multitude of joints. In addition to skeletal involvement, many other tissues and organ systems are affected, severely compromising quality of life. In the more severe cases, individuals with rheumatoid arthritis will die at a relatively young age due to systemic inflammation and peripheral tissue destruction.

Current therapies for

Osteoarthritis

Osteoarthritis is a more targeted disease than rheumatoid arthritis and usually involves a small number of articulating joints. It presents most often in a more elderly population, although individuals with traumatic joint injury in their younger years may also present with this disease. Depending on the stage and severity of the disease, inflammation may be found, although this is not as key a player in the pathology as it is in rheumatoid arthritis. Currently, individuals with this disease

Osteoporosis

Osteoporosis is a disease that primarily affects postmenopausal women and elderly men. Bone is a dynamic tissue that constantly turns over and is remodeled. Balance of bone-resorbing and bone-forming mechanisms is key to the maintenance of bone homeostasis. In osteoporosis this balance is compromised, resulting in increased bone resorption over bone formation. The currently available therapies inhibit bone resorption — agents include bisphosphonates and estrogenic compounds. In addition to

Conclusions

This volume describes a variety of musculoskeletal diseases and the targets that are under consideration for therapeutic development. Our understanding of these diseases and disease mechanisms is continuing to grow with the introduction of reagents, compounds and drugs that have been used to dissect the pathways involved. If current research efforts are sustained, it is anticipated that a number of new therapies will emerge over the next decade that will have significant beneficial effects on

Michael Lark has worked on cell/extracellular matrix interactions for the past 20 years. The majority of his career has been spent in industry where he has focused on bone and cartilage diseases. For the past six years Michael has been at GlaxoSmithKline, where he is currently Director of Musculoskeletal Diseases Biology, working on osteoporosis, osteoarthritis and rheumatoid arthritis. The focus of his department is to identify and validate targets of interest in these disease areas and to

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Michael Lark has worked on cell/extracellular matrix interactions for the past 20 years. The majority of his career has been spent in industry where he has focused on bone and cartilage diseases. For the past six years Michael has been at GlaxoSmithKline, where he is currently Director of Musculoskeletal Diseases Biology, working on osteoporosis, osteoarthritis and rheumatoid arthritis. The focus of his department is to identify and validate targets of interest in these disease areas and to profile compounds through animal pharmacology studies.

Karen Morrison trained in molecular genetics at Yale University and the University of Oxford, first working on inherited renal disease and then the motor nerve disorders of spinal muscular atrophy and amyotrophic lateral sclerosis. She took up the Chair in Clinical Neurology at the University of Birmingham in 1999, where she combines laboratory research on molecular mechanisms in neurodegenerative disorders with clinical neurology.

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