What Rare Diseases Can Tell Us About OA

Purpose: Rare cartilage diseases are a neglected area of study in osteoarthritis (OA). This presentation puts forward the proposition that more emphasis on studying rare cartilage syndromes could lead to accelerated progress in understanding OA and age-related joint degeneration. OA is one of the major causes of disability globally, yet despite the resources which have been channelled into research, there are no current therapies for OA and only a limited number of biomarkers.

Methods: Research on the extreme phenotypes observed in rare diseases can help elucidate the pathogeneses of more common disorders, a phenomenon recognised by William Harvey as long ago as the 17 ^th century. Harvey wrote to a colleague “⋯ 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”. In monogenic disorders, the phenotypes are often very severe and disease progress is rapid making it easy to identify pathological changes, both structural and biochemical. Several therapies for common diseases, including the blockbuster drugs statins and bisphosphonates, were discovered in part through the study of rare syndromes.

Results: Rare disease research is making a significant contribution to understanding bone turnover and to the development of new therapeutic agents to regulate bone formation and bone resorption. Whilst the potential impact on OA of studying rare cartilage syndromes has been less explored, recent research has revealed new insights into OA disease mechanisms. Analysis of rare mutations responsible for chondrodysplasias has identified genes such as GDF5, which plays a key role in skeletal development. Polymorphisms in this gene are associated with OA susceptibility. Mutation of the ANKH gene in chondrocalcinosis has highlighted the role that this gene plays in the physiological and pathological mineralisation of cartilage. The expression of ANKH, which codes for a pyrophosphate transporter is known to be dysregulated in OA. Investigation of the rare autosomal recessive disorder CACP has revealed the disease-causing mutation in the PRG4 gene which codes for the secreted mucin-like proteoglycan, lubricin.Alkaptonuria (AKU) is an autosomal recessive disease of tyrosine metabolism that inevitably leads to early onset, aggressive arthropathy. Joint destruction in AKU is caused by the deposition of ochronotic pigment in cartilage, but there are several parallels with the pathophysiology of OA. Studies on tissue samples from patients with AKU, and from mouse models of the disease, have revealed previously unrecognised microanatomical and biochemical changes in joints which have been subsequently detected in human OA. These include early changes in the integrity of collagen fibrils, the role of calcified cartilage in the initiation of OA, thinning and cracking of the subchondral plate and the formation of novel microanatomical structures including trabecular excrescences, templated by adipocytes, and high density mineralised protrusions (HDMPs). All these features are abundant and easily recognisable in the severe phenotype of AKU but have subsequently been found in common OA, where they contribute to joint destruction.

Conclusions: Studying rare cartilage diseases with extreme phenotypes can help elucidate pathophysiological mechanisms in OA.