Lessons from rare diseases of cartilage and bone

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Highlights

  • Studying rare syndromes helps elucidate disease mechanisms of more common disorders.

  • Lessons from rare bone diseases have contributed to the development of osteoanabolic therapies.

  • Osteoarthritis (OA) is a common disease with currently no effective therapies.

  • Investigation of rare cartilage syndromes is identifying new targets in OA.

  • HDMPs identified in AKU and then OA constitute a new mechanism of joint destruction.

Studying severe phenotypes of rare syndromes can elucidate disease mechanisms of more common disorders and identify potential therapeutic targets. Lessons from rare bone diseases contributed to the development of the most successful class of bone active agents, the bisphosphonates. More recent research on rare bone diseases has helped elucidate key pathways and identify new targets in bone resorption and bone formation including cathepsin K and sclerostin, for which drugs are now in clinical trials. By contrast, there has been much less focus on rare cartilage diseases and osteoarthritis (OA) remains a common disease with no effective therapy. Investigation of rare cartilage syndromes is identifying new potential targets in OA including GDF5 and lubricin. Research on the arthropathy of the ultra-rare disease alkaptonuria has identified several new features of the OA phenotype, including high density mineralized protrusions (HDMPs) which constitute a newly identified mechanism of joint destruction.

Introduction

Treasure your exceptions’ was advice dispensed to young scientists in 1908 by William Bateson during an inaugural lecture on his appointment as Professor of Biology in the University of Cambridge [1]. Bateson, one of the fathers of the science of genetics, was reiterating advice contained in a frequently quoted letter from William Harvey, the famous English medical scientist of the 17th century who is best known for his discovery of the circulation. Writing to John Vlackveld a Dutch physician, Harvey stated that ‘Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows tracings of her workings apart from the beaten paths; nor is there any better way to advance the proper practice of medicine than to give our minds to the discovery of the usual law of nature, by careful investigation of cases of rarer forms of disease’ [2]. The advice from Bateson and Harvey is good; the biomedical literature contains many examples of how physiological and pathophysiological mechanisms have been elucidated by careful investigation of the rarer forms of disease. Furthermore knowledge gained from rare disease research has made a major contribution to drug development and has the potential for much more impact. For example the development of the blockbuster drugs, statins was built on knowledge acquired through investigation of familial hypercholesterolemia and new targets including PCSK9 are under investigation [3]. The potential benefits from rare disease research, both scientific and commercial, led Cox to paraphrase Bateson's quote in the title of his article ‘Leading to the Treasure in Exceptions’ [4].

Why is the study of rare disease so influential? Mendelian diseases are nature's experimental gene knockouts of which there are more than 8000. They are often characterized by severe phenotypes with rapidly developing pathologies. Furthermore it is possible to trace the succession of pathophysiological events back to altered function of a single gene.

Section snippets

Lessons from rare diseases of bone

The value of rare disease research has been recognized and exploited with some success in bone. For example, the discovery of bisphosphonates (BPs) owes a debt to research on the hypophosphatasias (MIM 146300, 241500), which are caused by genetic deficiency of alkaline phosphatase and defective mineralization [5]. Investigation of these disorders led to the understanding of the role of pyrophosphate (PPi) in mineralization [6]. BPs were developed as non-hydrolysable analogues of PPi and are the

Lessons from rare diseases of cartilage

The spectacular progress made though rare diseases research in elucidating the physiology of bone turnover and the consequent identification of potential therapeutic targets to preserve and increase bone mass contrasts sharply with the position in osteoarthritis. OA is one of the major causes of disability in the developed world and the prevalence is increasing as the population ages. OA is the most significant disease for which there are no effective therapies. Treatment is limited to pain

Lessons from the arthropathy of alkaptonuria (AKU)

Our research has focused on the severe osteoarthropathy of the ultra-rare disease AKU [51], which has an iconic position in the history of medicine. AKU was the first human disease to be recognized to follow Mendelian inheritance by Archibald Garrod and was the prototype ‘inborn error of metabolism’ [52]. AKU results from homozygous or compound heterozygous mutations in the Hgd gene which codes for homogentisate dioxygenase (HGD), an enzyme in the tyrosine catabolic pathway. Deficiency of HGD,

Conclusion

We have reviewed the biomedical literature on the lessons learnt from rare diseases of bone and cartilage. Study of rare bone diseases has elucidated new important pathways in bone resorption and bone formation and led to the identification of a series of new potential therapeutic targets. There has been less research focus on investigation of rare cartilage syndromes, but several targets have been identified including GDF5 and lubricin. Our research on the arthropathy of the ultra-rare disease

Conflicts of interest

The authors have declared no conflicts of interest.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We are grateful to the AKU Society, the Rosetrees Foundation, the Childwick Trust and the Big Lottery for financial support. Drs Graham Davis, David Mills and Tomas Zikmund helped with our X-ray microtomographic studies.

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