Osteologie 2019; 28(01): 45
DOI: 10.1055/s-0039-1679964
Freie Vorträge Osteoonkologie
Georg Thieme Verlag KG Stuttgart · New York

Somatic activating mutations in MAP2K1 cause melorheostosis with highly porous lesions covered by compact periosteal bone

N Fratzl-Zelman
1  Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1st Medical Department Hanusch Hospital, Vienna
,
P Roschger
1  Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1st Medical Department Hanusch Hospital, Vienna
,
H Kang
2  Section on Heritable Disorders of Bone and Extracellular Matrix, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda
,
S Jha
3  Clinical and Investigative Orthopedics Surgery Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda
,
A Roschger
4  Max Planck Institute of Colloids and Interfaces, Department of Biomaterials, Potsdam
,
S Blouin
1  Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1st Medical Department Hanusch Hospital, Vienna
,
Z Deng
5  Biodata Mining and Discovery Section, Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda
,
WA Cabral
2  Section on Heritable Disorders of Bone and Extracellular Matrix, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda
,
A Ivovic
6  Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda
,
J Katz
7  National Institute of Arthritis and Musculoskeletal and Skin Diseases, Office of the Clinical Director, National Institutes of Health, Bethesda
,
RM Siegel
6  Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda
,
K Klaushofer
1  Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of WGKK and AUVA Trauma Center Meidling, 1st Medical Department Hanusch Hospital, Vienna
,
P Fratzl
4  Max Planck Institute of Colloids and Interfaces, Department of Biomaterials, Potsdam
,
T Bhattacharyya
3  Clinical and Investigative Orthopedics Surgery Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda
,
JC Marini
2  Section on Heritable Disorders of Bone and Extracellular Matrix, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda
› Author Affiliations
Further Information

Publication History

Publication Date:
05 March 2019 (online)

 

Introduction:

Somatic mosaic mutations in MAP2K1 have been recently identified as a cause of melorheostosis, a rare skeletal dysostosis with radiographic „dripping candle wax” appearance.

Methods:

We study the etiology of the disorder, based on in-vitro osteoblast differentiation and multi-method phenotype characterization of the bone material properties in biopsy samples obtained from affected and contralateral unaffected bone from six patients.

Results:

Investigation of affected bone by histology and micro-computed tomography reveal a distinctive morphology with a shell of primary bone formed by periosteal apposition, consisting of compact multi-layered bone lamellae oriented parallel to the outer surface. The deeper region comprises highly porous osteonal-like bone with a median pore diameter about 50 microns, corresponding to typical Haversian canals, highly elevated number of osteoblasts, osteoclasts and exuberant osteoid accumulation. Bone histomorphometry evaluations are consistent with in-vitro findings of increased cell proliferation and RANKL/OPG expression while BMP2-mediated differentiation and mineralization was markedly reduced. Quantitative backscattered electron imaging reveals an overall decreased mineral content (CaMean: -4.5%, P = 0.03) and an elevated amount of matrix undergoing primary mineralization (CaLow: +90%, P = 0.009) in affected bone. The periosteal bone is even less mineralized than the osteonal-like remodeled bone, possibly because the bone lamellae consist of younger tissue age. We further used the quantitative backscattered electron images to evaluate 2D-microporosity and found increased osteocyte lacunar porosity (+39%; P = 0.01). Finally, nano-indentation reveals a material hardness and stiffness strictly dependent on tissue mineralization (positive correlation with typical calcium concentration, CaPeak: r = 0.8984, P = 0.0150, and r = 0.9788, P = 0.0007, respectively) in the same manner in affected and unaffected bone.

Discussion:

We conclude that activating mutations in MAP2K1 oncogene lead to highly elevated bone turnover and gradual deterioration of bone microarchitecture due to increased tissue porosity and exuberant osteoid formation. This enhanced metabolic activity triggers a periosteal reaction of bone modeling leading to deposition of newly formed primary bone covering the lesion and resulting in an overall cortical outgrowth. The material properties of the lesions correlate with local variations in mineral content, depending on modeling and remodeling rates in the same way as normal bone.