SOCS2 is the critical regulator of GH action in murine growth plate chondrogenesis.
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(-/-) 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(-/-) 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 SOCS2(-/-) 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(-/-) 6-week-old mice as was the number of phosphorylated STAT-5-positive hypertrophic chondrocytes. The SOCS2(-/-) mouse represents a valid model for studying the local effects of GH on bone growth.
Bone Biology Group, Division of Developmental Biology, The Roslin Institute and Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Roslin, Midlothian, UK.
Chloe
C
Pass
Vicky Elizabeth
VE
MacRae
Carmen
C
Huesa
S
S
Faisal Ahmed
Colin
C
Farquharson
D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D020219:Chondrogenesis; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D013006:Growth Hormone / Q000378:metabolism* / Q000494:pharmacology; D006132:Growth Plate / Q000166:cytology / Q000378:metabolism*; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D008682:Metatarsal Bones / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*
D050791:STAT Transcription Factors; C491409:Socs2 protein, mouse; D050826:Suppressor of Cytokine Signaling Proteins; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone