Dysregulated miRNAs in bone cells of patients with Gorham‐Stout disease

Abstract

Gorham‐Stout disease (GSD) is a very rare disease characterized by increased bone erosion with angiomatous proliferation. The mechanisms underlying this disorder have not been deeply investigated. Due to its rarity, no guidelines are currently available for treatment and management of GSD. We recently evaluated the cellular alterations of the bone remodeling in patients showing that osteoclast precursors displayed increased ability to differentiate into osteoclasts and that affected osteoclasts resorb bone more actively than control cells. Moreover, osteoblasts isolated from a patient showed a defective ability to form mineralized nodules. In this paper, we investigated the molecular pathways involved in the cellular defects of GSD bone cells. For this study, we recruited nine patients and performed miRNome analysis of bone cells. Between the 178 miRNAs robustly expressed in GSD osteoclasts, significant modulation of three miRNAs (miR‐1246, miR‐1‐3p, and miR‐137‐3p) involved in the regulation of osteoclast formation and activity or in the angiomatous proliferation was found in patients' cells. Interestingly, miR‐1246 was also up‐regulated in serum exosomes from patients. Analysis of miRNAs from patient osteoblasts suggested alteration of miR‐204a‐5p, miR‐615‐3p and miR‐378a‐3p regulating osteoblast function and differentiation. The resulting miRNA pattern may help to understand better the mechanisms involved in GSD and to identify new potential therapeutic targets for this rare disease.

Gorham-Stout Disease with Multiple Bone Involvement—Challenging Diagnosis of a Rare Disease and Literature Review

“…There are no biomarkers available for GSD, but in some studies miRNAs and serum biomarkers were reported as possible biomarkers. There are studies that show changes in miRNAs in GSD, suggesting that these molecules could be used as potential biomarkers in GSD [ 27 ]. Some of these molecules of miRNAs (miR-1246, miR-137, and miR-1) are correlated with angiomatous proliferation and regulation of osteoclastogenesis and altered osteoclast morphology resulting in a more motile phenotype [ 27 ].…”

“…There are studies that show changes in miRNAs in GSD, suggesting that these molecules could be used as potential biomarkers in GSD [ 27 ]. Some of these molecules of miRNAs (miR-1246, miR-137, and miR-1) are correlated with angiomatous proliferation and regulation of osteoclastogenesis and altered osteoclast morphology resulting in a more motile phenotype [ 27 ]. Other miRNA molecules (miR-204-5p, miR-378a-3p, miR-615-3p, and miR-204-5p) play a role in inhibiting osteoblast differentiation and are elevated in GSD [ 27 ].…”

“…Some of these molecules of miRNAs (miR-1246, miR-137, and miR-1) are correlated with angiomatous proliferation and regulation of osteoclastogenesis and altered osteoclast morphology resulting in a more motile phenotype [ 27 ]. Other miRNA molecules (miR-204-5p, miR-378a-3p, miR-615-3p, and miR-204-5p) play a role in inhibiting osteoblast differentiation and are elevated in GSD [ 27 ]. Other potentially relevant and high serum biomarkers in GSD are pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen (ICTP; reflects increased bone resorption activity), sclerostin (associated with defective bone regeneration), VEGF-A (sign of angiomatous proliferation) and IL-6 (stimulates osteoclastogenesis and angiogenesis) [ 26 , 28 ].…”

Osteopathy in Complex Lymphatic Anomalies

“…Another possible explanation to determine the presence of lymphatics in bone could be due to abnormal LEC migration during development. This hypothesis could explain the reason why there are CLA subtypes that only affect trabecular bone (GLA/KLA) while also justifying the abnormal inherent characteristics found in bone cells isolated from GSD patients [ 54 , 67 , 68 , 92 , 93 , 94 ]. Further research focused on understanding the source of invading lymphatics might facilitate patient diagnosis and development of new treatments.…”

Stimulation of Treg Cells to Inhibit Osteoclastogenesis in Gorham-Stout Disease

“…Ten patients were recruited by the Rare Diseases and Medical Genetics Unit of Bambino Gesù Children's Hospital (OPBG). The description of nine patients was previously reported (Rossi et al, 2021). A 12 years old female patient with swelling of the frontal bone, osteolysis of frontal and parietal bone, vertebrae and left scapula has been recently recruited for this study (Supplementary Table 1).…”