SCF, BDNF, and Gas6 Are Regulators of Growth Plate Chondrocyte Proliferation and Differentiation

• Published in: Molecular endocrinology (Baltimore, Md.) Md.), 2010-01, Vol.24 (1), p.193-203
• Main Authors: Hutchison, Michele R, Bassett, Mary H, White, Perrin C
• Format: Article
• Language: English
• Subjects: Animals; Biomarkers - metabolism; Brain-Derived Neurotrophic Factor - physiology; Cattle; Cell Differentiation - drug effects; Cell Line; Cell Proliferation - drug effects; Cells, Cultured; Chondrocytes - classification; Chondrocytes - cytology; Chondrocytes - physiology; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene Expression Profiling; Growth Plate - cytology; Growth Plate - physiology; Insulin - pharmacology; Insulin-Like Growth Factor I - pharmacology; Intercellular Signaling Peptides and Proteins - physiology; Male; Mice; Oligonucleotide Array Sequence Analysis; Organ Specificity; Stem Cell Factor - physiology
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2009-0228

We previously demonstrated that bovine epiphyseal chondrocytes separated by density gradient centrifugation differ in proliferative response to IGF-I and IGF-I receptor number. To identify novel modifiers of IGF-I action at the growth plate, we used microarray analyses to compare bovine hypertrophic and reserve zones and identified several receptors differentially expressed across the growth plate: NTRK2 [receptor for brain-derived neurotrophic factor (BDNF)], KIT [receptor for stem cell factor (SCF)], and MER and AXL [two receptors for growth arrest-specific 6 (Gas6)]. The corresponding ligands were tested for their ability to stimulate either proliferation of isolated chondrocytes or differentiation in ATDC5 cells. Each factor inhibited IGF-I-mediated proliferation in isolated chondrocytes by attenuating ERK1/2 activation. SCF, BDNF, Gas6, and C-type natriuretic peptide promoted differentiation in ATDC5 cells, each factor producing different expression patterns for collagen X, collagen 2, aggrecan, and lysyl oxidase. Whereas multiple factors stimulated ATDC5 differentiation, only IGF-I and high-dose insulin, out of several factors implicated in chondrocyte maturation, stimulated proliferation of isolated chondrocytes. IGF-I appears to be the primary proliferative signal in growth plate chondrocytes, whereas multiple factors including SCF, BDNF, and Gas6 regulate the pace of differentiation at the growth plate. SCF, BDNF, Gas6 and CNP each inhibits IGF-I-stimulated growth plate chondrocyte proliferation by attenuating ERK1/2 activation and also stimulates chondrocyte differentiation.