NIH Publications
Read below for all publications from the “Study of the Natural History, Pathogenesis and Outcome of Melorheostosis – a Rare Osteosclerotic Disease.”
Unraveling melorheostosis: Insights into clinical features, diagnosis, and treatment.
Dr. Timothy BhattacharyyaA comprehensive look at the clinical features, diagnostic approaches, and current treatment options for melorheostosis, alongside future research directions aimed at improving patient outcomes.
CDK4 inhibition reduces proliferation and mineralization in MAP2K1+ melorheostosis: opening a pathway to treatment
Jyotirindra Maity, Gourinandan Saravanan, Fatemeh Navid, Sarthak Gupta, Robert A Colbert, Timothy BhattacharyyaPatients with melorheostosis have excessive bone growth, leading to pain and deformity. Using cells derived from patients, we show that the bone overgrowth may be due to cells rapidly dividing. When treated with palbociclib, a drug that inhibits cell division, these cells showed reduced growth and reduced bone formation in culture. While palbociclib is currently approved only for certain types of breast cancer, these findings indicate its potential for repurposing as a treatment for melorheostosis. However, further clinical studies are necessary to confirm its safety and effectiveness for this specific condition.
VEGF Secretion Drives Bone Formation in Classical MAP2K1+ Melorheostosis
Jules D Allbritton‐King, Jyotirindra Maity, Amit Patel, Robert A Colbert, Fatemeh Navid, Timothy BhattacharyyaResearchers developed a stem-cell model of melorheostosis using skin cells from patients with MAP2K1 mutations and found that affected bone-forming cells produce excessive amounts of VEGF, a protein that stimulates tissue growth and blood vessel formation. They showed that VEGF contributes to the abnormal bone overgrowth seen in melorheostosis and that blocking VEGF reduced abnormal bone mineralization in laboratory models, suggesting a potential new treatment approach for this rare disease.
Occupational engagement, fatigue, and upper and lower extremity abilities in persons with melorheostosis
Farrell K, Comis LE, Casimir MM, et al.Melorheostosis is a rare bone disorder with limited literature that describes the effect of this disease on functional and motor abilities. As part of a natural history study, four outcome measures were administered to better understand the burden this disease has on a person’s ability to engage in basic and instrumental activities of daily living. The results of this study underscore the importance of acknowledging activity domain, fatigue constructs, and lesion location to support and provide targeted evidence-based rehabilitative therapy.
Fibroblasts from Patients with Melorheostosis Promote Angiogenesis in Healthy Endothelial Cells through Secreted Factors
Amelia C. Hurley-Novatny, Jules D. Allbritton-King, Smita Jha, Edward W. Cowen, Robert A. Colbert, Fatemeh Navid, Timothy BhattacharyyaFibroblasts from patients with MAP2K1-positive melorheostosis produce abnormally high levels of pro-angiogenic factors, particularly VEGF, which stimulate healthy endothelial cells to form new blood vessels. Researchers showed that this increased angiogenesis is driven by overactivation of the MEK/ERK signaling pathway and can be reduced with the MEK inhibitor trametinib or the anti-VEGF drug bevacizumab, highlighting both pathways as potential therapeutic targets for treating melorheostosis.
Cross‐Sectional Imaging Useful in Melorheostosis
Hurley-Novatny A, Karantanas AH, Papadakis GZ, Bhattacharyya T, Jha SThis study demonstrated that cross-sectional imaging techniques such as CT and MRI provide valuable insights into the extent of bone and soft tissue involvement in melorheostosis, often revealing disease features that are not visible on standard X-rays. The authors showed that advanced imaging can improve diagnosis, help distinguish melorheostosis from other bone disorders, and support treatment planning by better characterizing the disease’s impact on surrounding tissues.
Somatic SMAD3-activating mutations cause melorheostosis by up-regulating the TGF-β/SMAD pathway.
Kang H, Jha S, Ivovic A, Fratzl-Zelman N, Deng Z, Mitra A, et al.The study identified somatic activating mutations in the SMAD3 gene in a subset of patients with melorheostosis, revealing a second genetic pathway responsible for the disease beyond the previously discovered MAP2K1 mutations. Researchers showed that these mutations increase activity in the TGF-β/SMAD signaling pathway, leading to abnormal bone formation and providing new insights into disease mechanisms and potential targets for future therapies.
Distribution and Functional Consequences of Somatic MAP2K1 Variants in Affected Skin Associated with Bone Lesions in Melorheostosis.
Jha S, Ivovic A, Kang H, Meylan F, Hanson EP, Rimland C, Lange E, Katz J, McBride A, Warner AC, Edmondson EF, Cowen EW, Marini JC, Siegel RM, Bhattacharyya TUses advanced imaging and tissue analysis to show that melorheostotic bone lesions caused by somatic MAP2K1 mutations have abnormal bone microarchitecture, including excessive bone remodeling, increased porosity, and prominent periosteal bone formation. The findings provided new insight into how MAP2K1 mutations alter bone development and structure, helping explain the pain, deformity, and characteristic radiographic appearance seen in many patients with melorheostosis.
Distinct clinical and pathological features of melorheostosis associated with somatic MAP2K1 mutations.
Jha S, Fratzl-Zelman N, Roschger P, Papadakis GZ, Cowen EW, Kang H, et al.Distinct forms of melorheostosis associated with somatic MAP2K1 mutations are found to be characterized by the classic “dripping candle wax” appearance on X-rays, overlying vascular skin changes, and increased involvement of joints and surrounding soft tissues. Researchers also found that affected bone showed unusually high bone remodeling, vascularity, and activity of bone-forming and bone-resorbing cells, helping to explain how MAP2K1 mutations drive the disease process.
Clinical evaluation of melorheostosis in the context of a natural history clinical study.
Jha S, Cowen EW, Lehky TJ, Alter K, Flynn L, Reynolds JC, et al.This natural history study of 30 adults with melorheostosis provided the most comprehensive clinical evaluation of the disease to date, documenting common symptoms such as pain, limited mobility, skin changes, and sensory nerve abnormalities. The findings highlighted the importance of multidisciplinary care—including orthopedic, neurological, dermatological, pain management, and rehabilitation specialists—and established a foundation for future research into diagnosis, disease progression, and treatment strategies.
Melorheostosis: A clinical, pathologic, and radiologic case series.
Allen CE, Fratzl-Zelman N, Roschger P, Klaushofer K, Jha S, Marini JC, et al.Examination of bone biopsies from 15 patients with melorheostosis and found that the disease exhibits several distinct microscopic patterns, including dense cortical bone, woven bone, increased vascularity, and abnormal bone remodeling. The study provided the most comprehensive description of melorheostosis pathology to date, helping clinicians and pathologists better recognize and diagnose the disease by combining histologic findings with clinical and radiologic features.
Melorheostotic Bone Lesions Caused by Somatic Mutations in MAP2K1 Have Deteriorated Microarchitecture and Periosteal Reaction.
Fratzl-Zelman N, Roschger P, Kang H, Jha S, et al.Summarizes the latest understanding of melorheostosis and osteopoikilosis, highlighting how advances in genetics have linked most cases of melorheostosis to somatic mutations in MAP2K1 and related signaling pathways. The authors described the disease’s clinical features, radiographic patterns, and treatment options while emphasizing how these genetic discoveries may lead to more targeted therapies in the future.
Somatic activating mutations in MAP2K1 cause melorheostosis.
Kang, H., Jha, S., Deng, Z. et al.This landmark study identified somatic mutations in the MAP2K1 gene as a major cause of sporadic melorheostosis, providing the first clear genetic explanation for many cases of the disease. Researchers found that these mutations occur only in affected bone tissue, leading to abnormal bone growth and remodeling, and their findings also highlighted the MEK/ERK signaling pathway as a promising target for future treatments.
CT analysis of anatomical distribution of melorheostosis challenges the sclerotome hypothesis.
Jha S, Laucis N, Kim L, Malayeri A, Dasgupta A, Papadakis GZ, et al.Using whole-body CT scans from 30 patients with melorheostosis to examine how the disease is distributed throughout the skeleton and found that its pattern rarely matched the long-standing “sclerotome hypothesis.” Instead, the findings suggest that melorheostosis is more likely caused by the clonal expansion of mutated skeletal progenitor cells during limb development, providing new insight into how the disease forms and spreads within affected bones.