Human stanniocalcin-1 or -2 expressed in mice reduces bone size and severely inhibits cranial intramembranous bone growth.
Stanniocalcin-1 (STC1) and -2 (STC2) are highly related, secreted, homodimeric glycoproteins that are significantly upregulated by different forms of stress including high phosphate levels. Transgenic mice that constitutively express either human STC1 or STC2 exhibit intra-uterine growth restriction and permanent post-natal growth retardation. STC1 is expressed in chondrocytic and osteoblastic cells during murine development and can enhance differentiation of calvarial cells in culture. Therefore, there is mounting evidence that stanniocalcins (STCs) modulate bone development in vivo. To further define the effects of stanniocalcins on skeletal development, we performed a series of measurements on components of the axial, appendicular, and cranial skeleton in transgenic and wildtype mice. We show that skeletal growth is retarded and that the intramembranous bones of the cranium exhibit a particularly severe delay in suture closure. The posterior frontal suture remains patent throughout the lifetime of human STC1 and STC2 transgenic mice. We did not observe significant effects on chondrogenesis: however, calvarial cells exhibited reduced viability, proliferation and delayed differentiation, indicating that developing osteoblasts are particularly sensitive to the levels of STCs. Given the evidence linking STC1 to cellular phosphate homeostasis, we assessed the expression of a variety of phosphate regulators in transgenic and wildtype calvarial cells and found significantly lower levels of Mepe, Dmp1, Sfrp4 in transgenic cells without a change in Pit1 or Pit2. Collectively these data support a direct regulatory role for STCs in osteoblasts and suggest that overexposure to these factors inhibits normal skeletal development without significant changes in patterning.
Johnston
Jennifer
J
Cancer Research Laboratory Program, London Regional Cancer Program (LRCP), 790 Commissioners Rd, Room A4-921, London, ON, N6A 4L6, Canada.
Ramos-Valdes
Yudith
Y
Stanton
Lee-Anne
LA
Ladhani
Sadia
S
Beier
Frank
F
Dimattia
Gabriel E
GE
D000818:Animals; D001483:Base Sequence; D001846:Bone Development / Q000235:genetics* / Q000502:physiology*; D003393:Cranial Sutures / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006023:Glycoproteins / Q000235:genetics* / Q000502:physiology*; D006132:Growth Plate / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology; D028061:Phosphate Transport Proteins / Q000378:metabolism; D011247:Pregnancy; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012886:Skull / Q000196:embryology / Q000254:growth & development* / Q000378:metabolism
D017931:DNA Primers; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D028061:Phosphate Transport Proteins; D011994:Recombinant Proteins; C114997:STC2 protein, human; C051795:teleocalcin