Phospholipase C signaling via the parathyroid hormone (PTH)/PTH-related peptide receptor is essential for normal bone responses to PTH.
We have previously shown that differentiation of hypertrophic chondrocytes is delayed in mice expressing a mutated PTH/PTHrP receptor (PTHR) (called DSEL here) that stimulates adenylyl cyclase normally but fails to activate phospholipase C (PLC). To better understand the role of PLC signaling via the PTHR in skeletal and mineral homeostasis, we examined these mice fed a normal or calcium-deficient diet. On a standard diet, DSEL mice displayed a modest decrease in bone mass. Remarkably, when fed a low-calcium diet or infused with PTH, DSEL mice exhibited strikingly curtailed peritrabecular stromal cell responses and attenuated new bone formation when compared with Wt mice. Attenuated in vitro colony formation was also observed in bone marrow cells derived from DSEL mice fed a low-calcium diet. Furthermore, PTH stimulated proliferation and increased mRNAs encoding cyclin D1 in primary osteoblasts derived from Wt but not from DSEL mice. Our data indicate that PLC signaling through the PTHR is required for skeletal homeostasis.
Guo
Jun
J
Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. hkronenberg@partners.org
Liu
Minlin
M
Yang
Dehong
D
Bouxsein
Mary L
ML
Thomas
Clare C
CC
Schipani
Ernestina
E
Bringhurst
F Richard
FR
Kronenberg
Henry M
HM
D000818:Animals; D000831:Animals, Newborn; D016723:Bone Remodeling / Q000187:drug effects / Q000235:genetics; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D002136:Calcium, Dietary / Q000494:pharmacology; D002478:Cells, Cultured; D004032:Diet; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010281:Parathyroid Hormone / Q000378:metabolism / Q000494:pharmacology*; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D010738:Type C Phospholipases / Q000378:metabolism / Q000502:physiology*
D002136:Calcium, Dietary; D010281:Parathyroid Hormone; D044168:Receptor, Parathyroid Hormone, Type 1; D010738:Type C Phospholipases