SOCS2 is the critical regulator of GH action in murine growth plate chondrogenesis

Abstract

Suppressor of Cytokine Signaling-2 (SOCS2) is a negative regulator of growth hormone (GH) signaling and bone growth via inhibition of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. This has been classically demonstrated by the overgrowth phenotype of SOCS2 À/À mice, which has normal systemic insulin-like growth factor 1 (IGF-1) levels. The local effects of GH on bone growth are equivocal, and therefore this study aimed to understand better the SOCS2 signaling mechanisms mediating the local actions of GH on epiphyseal chondrocytes and bone growth. SOCS2, in contrast to SOCS1 and SOCS3 expression, was increased in cultured chondrocytes after GH challenge. Gain-and loss-of-function studies indicated that GH-stimulated chondrocyte STATs-1, -3, and -5 phosphorylation was increased in SOCS2 À/À chondrocytes but not in cells overexpressing SOCS2. This increased chondrocyte STAT signaling in the absence of SOCS2 is likely to explain the observed GH stimulation of longitudinal growth of cultured SOCS2À/À embryonic metatarsals and the proliferation of chondrocytes within. Consistent with this metatarsal data, bone growth rates, growth plate widths, and chondrocyte proliferation were all increased in SOCS2 À/À 6-week-old mice as was the number of phosphorylated STAT-5-positive hypertrophic chondrocytes. The SOCS2 À/À mouse represents a valid model for studying the local effects of GH on bone growth. ß

Direct stimulation of bone mass by increased GH signalling in the osteoblasts of Socs2−/− mice

“…These data suggest that STAT 5 mediates GH anabolic actions on bone as reported for growth plate chondrocytes and linear bone growth (Teglund et al . 1998, Pass et al . 2012).…”

“…In keeping with previous studies, the cells were exposed to 500 ng/ml rhGH or 50 ng/ml rhIGF1 (both Bachem, Merseyside, UK) (DiGirolamo et al . 2007, Pass et al . 2012).…”

RECENT RESEARCH ON THE GROWTH PLATE: Recent insights into the regulation of the growth plate

“…Recent evidence suggests that SOCS2 acts locally at the growth plate to modulate GH signaling. Chondrocytes isolated from Socs2 −/− mice showed increased STATs phosphorylation upon incubation with GH (Pass et al 2012), while cells overexpressing SOCS2 did not. Similarly, GH was able to stimulate growth in fetal metatarsals isolated from Socs2 −/− mice, but not that from wild type mice (Pass et al 2012), suggesting local GH action at the growth plate is negatively regulated by SOCS2.…”

“…Chondrocytes isolated from Socs2 −/− mice showed increased STATs phosphorylation upon incubation with GH (Pass et al 2012), while cells overexpressing SOCS2 did not. Similarly, GH was able to stimulate growth in fetal metatarsals isolated from Socs2 −/− mice, but not that from wild type mice (Pass et al 2012), suggesting local GH action at the growth plate is negatively regulated by SOCS2. Some evidence suggests such local modulation of GH action is IGF-independent, since the GH-induced Socs2 −/− metatarsal bone growth is not accompanied by increase in Igf1 or Igfbp3 transcript levels, and occurred in the presence of an IGF-I receptor inhibitor (NVP-AEW541) ( Dobie et al 2013, unpublished).…”

Culture of Murine Embryonic Metatarsals: A Physiological Model of Endochondral Ossification

“…Our previous studies have utilized the metatarsal organ culture system to determine the role of suppressor of cytokine signalling-2 (SOCS2) in endochondral bone growth. Using metatarsal bones from mice deficient in SOCS2, we have shown that growth hormone is able to simulate their longitudinal growth independent of insulin like growth factor (IGF-1), unlike wild-type metatarsal bones which do not respond to growth hormone treatment 34,41 . This highlights the extent to which metatarsal cultures can be manipulated to examine the effects of different genes and/or exogenous factors on endochondral bone growth.…”