TY - JOUR
T1 - Investigating the role of ASCC1 in the causation of bone fragility.
AU - Voraberger, Barbara
AU - Mayr, Johannes A.
AU - Fratzl-Zelman, Nadja
AU - Blouin, Stéphane
AU - Uday, Suma
AU - Kopajtich, Robert
AU - Koedam, Marijke
AU - Hödlmayr, Helena
AU - Wortmann, Saskia
AU - Csillag, Bernhard
AU - Prokisch, Holger
AU - van der Eerden, Bram C J
AU - El-Gazzar, Ahmed
AU - Högler, Wolfgang
N1 - Mayr, Wortmann: University Children's Hospital Salzburg, Paracelsus Medical University Salzburg, Salzburg, Austria
PY - 2023
Y1 - 2023
N2 - Bi-allelic variants in ASCC1 cause the ultrarare bone fragility disorder "spinal muscular atrophy with congenital bone fractures-2" (SMABF2). However, the mechanism by which ASCC1 dysfunction leads to this musculoskeletal condition and the nature of the associated bone defect are poorly understood. By exome sequencing, we identified a novel homozygous deletion in ASCC1 in a female infant. She was born with severe muscular hypotonia, inability to breathe and swallow, and virtual absence of spontaneous movements; showed progressive brain atrophy, gracile long bones, very slender ribs, and a femur fracture; and died from respiratory failure aged 3 months. A transiliac bone sample taken postmortem revealed a distinct microstructural bone phenotype with low trabecular bone volume, low bone remodeling, disordered collagen organization, and an abnormally high bone marrow adiposity. Proteomics, RNA sequencing, and qPCR in patient-derived skin fibroblasts confirmed that ASCC1 was hardly expressed on protein and RNA levels compared with healthy controls. Furthermore, we demonstrate that mutated ASCC1 is associated with a downregulation of RUNX2, the master regulator of osteoblastogenesis, and SERPINF1, which is involved in osteoblast and adipocyte differentiation. It also exerts an inhibitory effect on TGF-β/SMAD signaling, which is important for bone development. Additionally, knockdown of ASCC1 in human mesenchymal stromal cells (hMSCs) suppressed their differentiation capacity into osteoblasts while increasing their differentiation into adipocytes. This resulted in reduced mineralization and elevated formation of lipid droplets. These findings shed light onto the pathophysiologic mechanisms underlying SMABF2 and assign a new biological role to ASCC1 acting as an important pro-osteoblastogenic and anti-adipogenic regulator.
AB - Bi-allelic variants in ASCC1 cause the ultrarare bone fragility disorder "spinal muscular atrophy with congenital bone fractures-2" (SMABF2). However, the mechanism by which ASCC1 dysfunction leads to this musculoskeletal condition and the nature of the associated bone defect are poorly understood. By exome sequencing, we identified a novel homozygous deletion in ASCC1 in a female infant. She was born with severe muscular hypotonia, inability to breathe and swallow, and virtual absence of spontaneous movements; showed progressive brain atrophy, gracile long bones, very slender ribs, and a femur fracture; and died from respiratory failure aged 3 months. A transiliac bone sample taken postmortem revealed a distinct microstructural bone phenotype with low trabecular bone volume, low bone remodeling, disordered collagen organization, and an abnormally high bone marrow adiposity. Proteomics, RNA sequencing, and qPCR in patient-derived skin fibroblasts confirmed that ASCC1 was hardly expressed on protein and RNA levels compared with healthy controls. Furthermore, we demonstrate that mutated ASCC1 is associated with a downregulation of RUNX2, the master regulator of osteoblastogenesis, and SERPINF1, which is involved in osteoblast and adipocyte differentiation. It also exerts an inhibitory effect on TGF-β/SMAD signaling, which is important for bone development. Additionally, knockdown of ASCC1 in human mesenchymal stromal cells (hMSCs) suppressed their differentiation capacity into osteoblasts while increasing their differentiation into adipocytes. This resulted in reduced mineralization and elevated formation of lipid droplets. These findings shed light onto the pathophysiologic mechanisms underlying SMABF2 and assign a new biological role to ASCC1 acting as an important pro-osteoblastogenic and anti-adipogenic regulator.
KW - EPITHELIUM-DERIVED FACTOR
KW - IMPERFECTA TYPE VI
KW - OSTEOBLAST DIFFERENTIATION
KW - NORMATIVE DATA
KW - CELL FATE
KW - IDENTIFICATION
KW - ADIPOGENESIS
KW - COMPLEX
KW - CBFA1
KW - JUN
U2 - 10.3389/fendo.2023.1137573
DO - 10.3389/fendo.2023.1137573
M3 - Original Article
C2 - 37455927
SN - 1664-2392
VL - 14
SP - 1137573
JO - FRONTIERS IN ENDOCRINOLOGY
JF - FRONTIERS IN ENDOCRINOLOGY
ER -