Abstract
Human linkage studies suggest that craniofacial deformities result from either genetic mutations related to cholesterol metabolism or high-cholesterol maternal diets. However, little is known about the precise roles of intracellular cholesterol metabolism in the development of craniofacial bones, the majority of which are formed through intramembranous ossification. Here, we show that an altered cholesterol metabolic status results in abnormal osteogenesis through dysregulation of primary cilium formation during bone formation. We found that cholesterol metabolic aberrations, induced through disruption of either Dhcr7 (which encodes an enzyme involved in cholesterol synthesis) or Insig1 and Insig2 (which provide a negative feedback mechanism for cholesterol biosynthesis), result in osteoblast differentiation abnormalities. Notably, the primary cilia responsible for sensing extracellular cues were altered in number and length through dysregulated ciliary vesicle fusion in Dhcr7 and Insig1/2 mutant osteoblasts. As a consequence, WNT/β-catenin and hedgehog signaling activities were altered through dysregulated primary cilium formation. Strikingly, the normalization of defective cholesterol metabolism by simvastatin, a drug used in the treatment of cholesterol metabolic aberrations, rescued the abnormalities in both ciliogenesis and osteogenesis in vitro and in vivo. Thus, our results indicate that proper intracellular cholesterol status is crucial for primary cilium formation during skull formation and homeostasis.
Highlights
Cellular cholesterol amounts are regulated by multiple steps of biosynthesis and feedback mechanisms.[1]
We found that Col1a1 gene cholesterol and cholesterol intermediates) can regulate bone expression was significantly and consistently downregulated in development through modulation of primary cilium formation frontal bones of Insig1/2 conditional KO (cKO) mice at E14.5, E16.5 and P0 (Fig. 2c), and function
Our results indicate that Dhcr[7] and Insig1/2 play an important role in primary cilium formation
Summary
Cellular cholesterol amounts are regulated by multiple steps of biosynthesis and feedback mechanisms.[1]. The 7-dehydrocholesterol reductase (DHCR7) catalyzes the final step of cholesterol biosynthesis;[8] mutations in DHCR7 cause cholesterol deficiency and an excess of cholesterol precursors, resulting in craniofacial deformities (e.g., microcephaly, cleft palate, craniosynostosis, and micrognathia), intellectual disability, and behavioral problems in humans.[9,10] Dhcr7−/− mice show a suckling defect, weight less, immature lungs, distended bladders, and variable craniofacial abnormalities.[11] The molecular mechanism of craniofacial anomalies in these conditions is still elusive. Mice deficient for Insig[1] and Insig[2] (Insig1−/ −;Insig2−/− mice), which are negative regulators of cholesterol biosynthesis,[13] show high-cholesterol levels in craniofacial tissues and display craniofacial deformities such as midfacial cleft, cleft palate, calvarial deformities and micrognathia, while mice deficient for either Insig[1] or Insig[2] are normal.[3,12] These craniofacial deformities are rescued by the normalization of cholesterol levels in Insig1/2 null mice;[3] it remains elusive how high-cholesterol levels cause craniofacial deformities and which cells are responsible for the craniofacial anomalies seen in
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