A collaborative study lead by researchers at the Mater Research Institute-The University of Queensland (MRI-UQ) has described a novel ‘roadmap’ of bone formation in the small bones of the hand to better inform future investigation of the underlying pathological features of skeletal dysplasias.
The study, published in The American Journal of Pathology1, found that a subgroup of related carpal-tarsal osteolysis syndromes (CTOS), which have historically been characterised as syndromes caused by abnormal bone loss, may actually be the result of impaired bone formation.
Skeletal dysplasias are rare genetic disorders causing abnormal skeletal development and growth. In multicentric carpal-tarsal osteolysis; multicentric osteolysis, nodulosis and arthropathy (also called Torg syndrome); and Winchester syndrome patients typically present with wrist and/or feet swelling in early childhood.
Although each of these CTOS are caused by mutations in different genes, they are all characterised by site-specific bone abnormalities with progressive loss on X-ray of the small bones in the hands and feet as well as the ends (epiphyses) of many long bones. To date, the apparent bone loss has been assumed to be a consequence of excessive bone destruction or osteolysis. However, the underlying genetic causes of these CTOS was very difficult to reconcile with the observed site-specific impacts.
MRI-UQ researcher and lead author Associate Professor Allison Pettit said the findings of the study change the understanding of these CTOS and will potentially have a broader impact on other skeletal conditions.
“What we have shown in this study is that all the hand bone sites that are specifically affected in the CTOS of interest, are formed by a little known type of bone formation, subarticular ossification, which differs from the more common physeal endochondral ossification that occurs at most other skeletal sites. We also showed that the proteins of the three genes mutated in each of the CTOS of interest were expressed in the bones undergoing subarticular ossification providing evidence of potential direct causality.” A/Prof Pettit said.
“Our findings provide a valuable roadmap for future investigation into the disordered processes of these syndromes and make a strong case for the underlying abnormality of these CTOS being dysregulated bone formation rather than inflammation-driven bone loss.
“If correct, this would completely flip our understanding of these conditions and have striking implications for not only their classification, but also for the treatment of these CTOS.
“Previous treatment approaches have included blocking bone destruction (bisphosphonates), with only anecdotal improvement in pain and swelling in some cases but no objective evidence of altered disease progression. Similarly, anti-inflammatory (glucocorticoid therapy, NSAIDs) or immunomodulatory therapy has provided symptom relief but not altered the bone phenotype or disease progression,” A/Prof Pettit said.
“While more research is needed to confirm and extend this study, it provides a compelling explanation for the disappointing efficacy of treatments targeted at preventing bone loss in these specific CTOS and even cautions against their use given the associated potential side-effects.”
MRI-UQ collaborated with UQ Diamantina Institute, Queensland University of Technology and the Royal Brisbane and Women’s Hospital Department of Endocrinology on this study.
The American Journal of Pathology has selected data from this paper for the journal volume cover image.
1Syndia Lazarus, Hsu-Wen Tseng, Felicity Lawrence, Maria Ann Woodruff, Emma Letitia Duncan, Allison Robyn Pettit. Characterization of Normal Murine Carpal Bone Development Prompts Re-Evaluation of Pathologic Osteolysis as the Cause of Human Carpal-Tarsal Osteolysis Disorders. American Journal of Pathology, July 2017.
http://ajp.amjpathol.org/article/S0002-9440(16)30602-2/fulltext