Abstract
Growth of long bones and vertebrae is maintained postnatally by a long-lasting pool of progenitor cells. Little is known about the molecular mechanisms that regulate the output and maintenance of the cells that give rise to mature cartilage. Here we demonstrate that postnatal chondrocyte-specific deletion of a transcription factor Stat3 results in severely reduced proliferation coupled with increased hypertrophy, growth plate fusion, stunting and signs of progressive dysfunction of the articular cartilage. This effect is dimorphic, with females more strongly affected than males. Chondrocyte-specific deletion of the IL-6 family cytokine receptor gp130, which activates Stat3, phenocopied Stat3-deletion; deletion of Lifr, one of many co-receptors that signals through gp130, resulted in a milder phenotype. These data define a molecular circuit that regulates chondrogenic cell maintenance and output and reveals a pivotal positive function of IL-6 family cytokines in the skeletal system with direct implications for skeletal development and regeneration.
Highlights
Growth of long bones and vertebrae is maintained postnatally by a long-lasting pool of progenitor cells
Interrogation of this longitudinal data set for IL-6 family cytokines and receptors, known regulators of STAT3 activity, demonstrated consistent expression of gp[130] and stage-specific expression of LIF to fetal and adolescent stages, during which growth plates are active in humans (Supplementary Fig. 1)
To understand the function of STAT3 during these stages, we knocked down STAT3 gene expression with lentiviral shRNA in human fetal chondrocytes isolated from the interzone at 15–17 weeks of development and compared their transcriptome to control cells (Fig. 1a)
Summary
Growth of long bones and vertebrae is maintained postnatally by a long-lasting pool of progenitor cells. We demonstrate that postnatal chondrocyte-specific deletion of a transcription factor Stat[3] results in severely reduced proliferation coupled with increased hypertrophy, growth plate fusion, stunting and signs of progressive dysfunction of the articular cartilage. This effect is dimorphic, with females more strongly affected than males. Newton et al defined a population of chondrogenic cells localized to the growth plate that generate clonal progeny and support long bone growth[9] Their data supported previous work showing that Hedgehog (Hh) signaling is required for growth plate maintenance; if this pathway is inhibited, growth plates fuse and differentiate into trabecular bone[10]. These results highlight the need for controlled, sustained proliferation of chondroprogenitors to maintain active growth plates
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