A-raf and B-raf are dispensable for normal endochondral bone development, and parathyroid hormone-related peptide suppresses extracellular signal-regulated kinase activation in hypertrophic chondrocytes.
Parathyroid hormone-related peptide (PTHrP) and the parathyroid hormone-PTHrP receptor increase chondrocyte proliferation and delay chondrocyte maturation in endochondral bone development at least partly through cyclic AMP (cAMP)-dependent signaling pathways. Because data suggest that the ability of cAMP to stimulate cell proliferation involves the mitogen-activated protein kinase kinase kinase B-Raf, we hypothesized that B-Raf might mediate the proliferative action of PTHrP in chondrocytes. Though B-Raf is expressed in proliferative chondrocytes, its conditional removal from cartilage did not affect chondrocyte proliferation and maturation or PTHrP-induced chondrocyte proliferation and PTHrP-delayed maturation. Similar results were obtained by conditionally removing B-Raf from osteoblasts. Because A-raf and B-raf are expressed similarly in cartilage, we speculated that they may fulfill redundant functions in this tissue. Surprisingly, mice with chondrocytes deficient in both A-Raf and B-Raf exhibited normal endochondral bone development. Activated extracellular signal-regulated kinase (ERK) was detected primarily in hypertrophic chondrocytes, where C-raf is expressed, and the suppression of ERK activation in these cells by PTHrP or a MEK inhibitor coincided with a delay in chondrocyte maturation. Taken together, these results demonstrate that B-Raf and A-Raf are dispensable for endochondral bone development and they indicate that the main role of ERK in cartilage is to stimulate not cell proliferation, but rather chondrocyte maturation.
Provot
Sylvain
S
Massachusetts General Hospital-Harvard Medical School, Endocrine Unit, 50 Blossom Street, Thier 1101, Boston, MA 02114-2696, USA.
Nachtrab
Gregory
G
Paruch
Jennifer
J
Chen
Adele Pin
AP
Silva
Alcino
A
Kronenberg
Henry M
HM
D000818:Animals; D001842:Bone and Bones / Q000378:metabolism*; D002356:Cartilage / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006984:Hypertrophy / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010012:Osteogenesis; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism*; D048491:Proto-Oncogene Proteins A-raf / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D044162:Parathyroid Hormone-Related Protein; D048491:Proto-Oncogene Proteins A-raf; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases