Hedgehog Signaling Modulates Cholesterol Homeostasis in Chondrocytes and in Osteoarthritis
Osteoarthritis (OA) is a common degenerative disease of the joint that is characterized by degradation and calcification of articular cartilage, and subchondral bone changes. Hedgehog (Hh) signaling is known to be activated in human and murine OA. Since Hh signaling regulates Gli-mediated gene expression, we identified Hh target genes that are expressed in chondrocytes. Microarray analyses were performed to detect changes in gene expression when the Hh pathway was modulated in human OA cartilage samples. Results from the Affymetrix Human Gene 1.0 ST microarray were analyzed for differentially expressed genes from three patient samples. Using Ingenuity® Pathway analysis, several genes known to be involved in sterol homeostasis were found to be modulated with Hh inhibition. We hypothesized that Hh signaling regulates cholesterol biosynthesis in chondrocytes, and that modulating cholesterol homeostasis impacts the severity of OA. To investigate the function of cholesterol in the cartilage, mice with chondrocyte-specific cholesterol accumulation were generated. This was achieved by excising Insig1 and Insig2, major negative regulators of cholesterol homeostasis. Over time, mice with chondrocyte-specific cholesterol accumulation exhibited impaired growth of the long bones. With aging or surgically induced joint instability, these mice developed more severe OA than control littermates. They expressed typical OA markers, such as type X collagen, indicating chondrocyte hypertrophy in the articular cartilage. Genetic manipulation of Hh signaling in these mice suggests that Hh signaling is modulating the phenotype by regulating sterol homeostasis. Hh reduction and statin treatment both lowered cholesterol production and rescued the phenotype, reducing the severity of OA. Here we identified novel Hh target genes in chondrocytes which regulate intracellular cholesterol levels, and found that cholesterol dysregulation in the chondrocytes predisposes to OA. These data suggest that pharmacologic correction of intra-articular sterol imbalance can be used as a treatment for osteoarthritis.
cartilage, cholesterol, Hedgehog signaling, microarray, osteoarthritis, statin
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