Lessons from rare diseases of cartilage and bone
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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Ultrastructural, material and crystallographic description of endophytic masses – A possible damage response in shark and ray tessellated calcified cartilage
2017, Journal of Structural BiologyCitation Excerpt :HDMPs, described recently in human and racehorse joint cartilage, are abnormal mineralized protrusions of the calcified cartilage layer surmounting the bone, jutting into the superficial unmineralized hyaline cartilage (Fig. 11C, D) (Boyde et al., 2011, 2014). It appears that HDMPs form in the cracks in the subchondral plate that follow abnormal cartilage matrix stiffening, which can be caused by age- or disease-related modifications of the proteoglycans that typically protect collagens and inhibit mineralization of cartilage (Gallagher et al., 2015). Like EPMs, HDMPs exhibit comparatively high mineral density and grow endophytically into uncalcified cartilage.
Comparative proteomics in alkaptonuria provides insights into inflammation and oxidative stress
2016, International Journal of Biochemistry and Cell BiologyCitation Excerpt :As for the damage to the spine and large joints, the arthritis observed in AKU resembles ankylosing spondylitis (http://www.ncbi.nlm.nih.gov/books/NBK1454/). For its progressive nature, with silent initial stages and extensive deterioration of cartilage and joints often found at time of diagnosis, AKU mimics the more common OA, though the deposition of ochronotic pigment in joints leads to an earlier onset of severe osteoarthropathy (Fernandez-Puente et al., 2011; Gallagher et al., 2015a; Zhao et al., 2009). Over the past decade, proteome techniques were successfully applied to a range of biological samples in the search of biomarkers (with diagnostic and prognostic value) and treatment targets for OA (Hsueh et al., 2014) and RA (Park et al., 2015).
Alkaptonuria: An example of a "fundamental disease"-A rare disease with important lessons for more common disorders
2016, Seminars in Cell and Developmental BiologyCitation Excerpt :Interestingly adipocytes seem to play a role in the formation of trabecular excrescences either by direct contribution to synthesis or by templating the formation of bone by osteoblasts. Perhaps the most significant lesson from ochronosis to date has been identification of high density mineralised protrusions (HDMPs) [23,24]. The first detection of these structures in human joints was in a 50 year old male with AKU who had hip arthroplasty because of lancinating pain in his hip joint.
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2015, Current Opinion in PharmacologyCell and tissue models of alkaptonuria
2020, Drug Discovery Today: Disease ModelsCitation Excerpt :Finding a cure able to address the complications observed in AKU would significantly improve patients’ quality of life. At the same time, since AKU can be considered a model for more common rheumatic conditions such as osteoarthritis (OA) [17], the social and economic impact of studying AKU would be much wider. Therefore, the development of suitable models able to reproduce AKU becomes fundamental.