Study Results Offer Potential Treatment Targets for Melorheostosis

Results from a study published in Nature Communications offer potential treatment targets for melorheostosis, often referred to as “dripping candle wax” bone disease.¹

The rare disorder earned the nickname because it causes excess bone formation that resembles dripping candle wax when shown on x-rays, and the new information may provide important clues about bone development and lead to insights about fracture healing and osteoporosis.

Researchers from the National Institute on Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at the National Institutes of Health (NIH) worked with 15 patients from around with world to uncover a genetic basis for the condition, and their work, chronicled in an article titled “Somatic activating mutations in MAP2K1 cause melorheostosis,” provides evidence that the bone disease can be the result of mutations in the MAP2K1 gene, which produces the MEK1 protein.

“Scientists previously assumed that the genetic mutations responsible for melorheostosis occurred in all cells of a person with the disorder,” said co-senior author Timothy Bhattacharyya, M.D., head of the Clinical and Investigative Orthopaedics Surgery Unit at the NIAMS in a press release. “Our team hypothesized that mutations might only occur in the affected bone tissue.”

“Most adults have the problem of weakening bones as they grow older. These patients have the opposite problem as some of their bones are rock hard and still growing,” said Bhattacharyya. “The prospect that we could somehow harness this pathway in the future is so exciting.”²

The MAP2K1 gene has previously been linked to some types of cancerous growths, as well as to conditions that result in abnormal blood vessel formation in the head and neck. In melorheostosis, all identified MAP2K1 mutations affect a region of the MEK1 protein that typically suppresses its activity, thus causing MEK1 to become overactive.

In the study, samples of affected and unaffected bone from 15 participants were biopsied, compared and evaluated for differences in the exome, which allowed for the team of researchers to pinpoint even the lowest levels of the mutations. In the analysis, it was revealed that 53.3% (n=8) of participants had mutations in the MAP2K1 gene in the affected bone only.

“This is an exciting study of a very rare bone disorder that not only identified the responsible mutation in half of the patients, but uncovered fundamental information about the role of a cancer-related gene in the metabolic pathways of normal bone,” said study co-senior author Joan Marini, Ph.D., M.D., of NICHD. “When we started, we had no preconceived causative pathways, but the participation of the patients has really changed the scientific landscape on this topic. Further studies on how this pathway works in both normal and mutant bone cells may have broad implications that could benefit a wider population.”

Findings from the study suggest that mutations in the overlying skin can raise the possibility that testing of skin for MAP2K1 mutations may be a diagnostic test for melorheostosis, however, if the skin sample returns negative, bone biopsy may still be necessary to detect the mutation, especially in patients with a low mutant allele frequency.

Study authors note that further evaluation of the MEK1-ERK1/2 pathway could potentially lead to insights pertinent to diseases where bone formation is weakened, such as delayed fracture healing and osteoporosis because melorheostosis is one of few osteosclerotic bone-forming diseases.

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References:

1. Kang H, Smita J, et al; Somatic activating mutations in MAP2K1 causes melorheostosis. Nature Communications. 2018;1390. doi: 10.1038/s41467-018-03720-z
2. NIH researchers crack mystery behind rare bone disorder [news release]. Bethesda, MD: National Institutes of Health; April 11, 2018. https://www.nih.gov/news-events/news-releases/nih-researchers-crack-mystery-behind-rare-bone-disorder