Intracellular biosynthesis of lipids and cholesterol by Scap and Insig in mesenchymal cells regulates long bone growth and chondrocyte homeostasis.
Hidetoshi Tsushima, Yuning J Tang, Vijitha Puviindran, Shu-Hsuan Claire Hsu, Puviindran Nadesan, Chunying Yu, Hongyuan Zhang, Anthony J Mirando, Matthew J Hilton, Benjamin A Alman
Author Information
Hidetoshi Tsushima: Department of Orthopaedic Surgery and Regeneration Next Initiative, Duke University, Durham, NC 27710, USA.
Yuning J Tang: Department of Orthopaedic Surgery and Regeneration Next Initiative, Duke University, Durham, NC 27710, USA.
Vijitha Puviindran: Department of Orthopaedic Surgery and Regeneration Next Initiative, Duke University, Durham, NC 27710, USA.
Shu-Hsuan Claire Hsu: Department of Orthopaedic Surgery and Regeneration Next Initiative, Duke University, Durham, NC 27710, USA.
Puviindran Nadesan: Department of Orthopaedic Surgery and Regeneration Next Initiative, Duke University, Durham, NC 27710, USA.
Chunying Yu: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Hongyuan Zhang: Department of Orthopaedic Surgery and Regeneration Next Initiative, Duke University, Durham, NC 27710, USA.
Anthony J Mirando: Department of Orthopaedic Surgery and Regeneration Next Initiative, Duke University, Durham, NC 27710, USA.
Matthew J Hilton: Department of Orthopaedic Surgery and Regeneration Next Initiative, Duke University, Durham, NC 27710, USA.
Benjamin A Alman: Department of Orthopaedic Surgery and Regeneration Next Initiative, Duke University, Durham, NC 27710, USA ben.alman@duke.edu. ORCID
During enchondral ossification, mesenchymal cells express genes regulating the intracellular biosynthesis of cholesterol and lipids. Here, we have investigated conditional deletion of or of and (Scap inhibits intracellular biosynthesis and Insig proteins activate intracellular biosynthesis). Mesenchymal condensation and chondrogenesis was disrupted in mice lacking in mesenchymal progenitors, whereas mice lacking the Insig genes in mesenchymal progenitors had short limbs, but normal chondrogenesis. Mice lacking in chondrocytes showed severe dwarfism, with ectopic hypertrophic cells, whereas deletion of Insig genes in chondrocytes caused a mild dwarfism and shortening of the hypertrophic zone. studies showed that intracellular cholesterol in chondrocytes can derive from exogenous and endogenous sources, but that exogenous sources cannot completely overcome the phenotypic effect of deficiency. Genes encoding cholesterol biosynthetic proteins are regulated by Hedgehog (Hh) signaling, and Hh signaling is also regulated by intracellular cholesterol in chondrocytes, suggesting a feedback loop in chondrocyte differentiation. Precise regulation of intracellular biosynthesis is required for chondrocyte homeostasis and long bone growth, and these data support pharmacological modulation of cholesterol biosynthesis as a therapy for select cartilage pathologies.
