PMID- 38530370
OWN - NLM
STAT- MEDLINE
DCOM- 20240508
LR  - 20240509
IS  - 2379-3708 (Electronic)
IS  - 2379-3708 (Linking)
VI  - 9
IP  - 9
DP  - 2024 Mar 26
TI  - Galpha11 deficiency increases fibroblast growth factor 23 levels in a mouse model of 
      familial hypocalciuric hypercalcemia.
LID - e178993 [pii]
LID - 10.1172/jci.insight.178993 [doi]
AB  - Fibroblast growth factor 23 (FGF23) production has recently been shown to 
      increase downstream of Galphaq/11-PKC signaling in osteocytes. Inactivating mutations 
      in the gene encoding Galpha11 (GNA11) cause familial hypocalciuric hypercalcemia 
      (FHH) due to impaired calcium-sensing receptor signaling. We explored the effect 
      of Galpha11 deficiency on FGF23 production in mice with heterozygous (Gna11+/-) or 
      homozygous (Gna11-/-) ablation of Gna11. Both Gna11+/- and Gna11-/- mice 
      demonstrated hypercalcemia and mildly raised parathyroid hormone levels, 
      consistent with FHH. Strikingly, these mice also displayed increased serum levels 
      of total and intact FGF23 and hypophosphatemia. Gna11-/- mice showed augmented 
      Fgf23 mRNA levels in the liver and heart, but not in bone or bone marrow, and 
      also showed evidence of systemic inflammation with elevated serum IL-1beta levels. 
      Furin gene expression was significantly increased in the Gna11-/- liver, 
      suggesting enhanced FGF23 cleavage despite the observed rise in circulating 
      intact FGF23 levels. Gna11-/- mice had normal renal function and reduced serum 
      levels of glycerol-3-phosphate, excluding kidney injury as the primary cause of 
      elevated intact FGF23 levels. Thus, Galpha11 ablation caused systemic inflammation 
      and excess serum FGF23 in mice, suggesting that patients with FHH - at least 
      those with GNA11 mutations - may be at risk for these complications.
FAU - Ay, Birol
AU  - Ay B
AD  - Endocrine Unit, Department of Medicine, and.
FAU - Cyr, Sajin Marcus
AU  - Cyr SM
AD  - Endocrine Unit, Department of Medicine, and.
FAU - Klovdahl, Kaitlin
AU  - Klovdahl K
AD  - Endocrine Unit, Department of Medicine, and.
FAU - Zhou, Wen
AU  - Zhou W
AD  - Endocrine Unit, Department of Medicine, and.
AD  - Nephrology Division, Massachusetts General Hospital, Harvard Medical School, 
      Boston, Massachusetts, USA.
FAU - Tognoni, Christina M
AU  - Tognoni CM
AD  - Department of Veterans Affairs, VA Boston Healthcare System, Boston, 
      Massachusetts, USA.
AD  - Department of Neurology, Boston University School of Medicine, Boston, 
      Massachusetts, USA.
FAU - Iwasaki, Yorihiro
AU  - Iwasaki Y
AD  - Endocrine Unit, Department of Medicine, and.
FAU - Rhee, Eugene P
AU  - Rhee EP
AD  - Endocrine Unit, Department of Medicine, and.
AD  - Nephrology Division, Massachusetts General Hospital, Harvard Medical School, 
      Boston, Massachusetts, USA.
FAU - Dedeoglu, Alpaslan
AU  - Dedeoglu A
AD  - Department of Veterans Affairs, VA Boston Healthcare System, Boston, 
      Massachusetts, USA.
AD  - Department of Neurology, Boston University School of Medicine, Boston, 
      Massachusetts, USA.
AD  - Department of Radiology, Massachusetts General Hospital and Harvard Medical 
      School, Massachusetts, USA.
FAU - Simic, Petra
AU  - Simic P
AD  - Endocrine Unit, Department of Medicine, and.
AD  - Nephrology Division, Massachusetts General Hospital, Harvard Medical School, 
      Boston, Massachusetts, USA.
FAU - Bastepe, Murat
AU  - Bastepe M
AD  - Endocrine Unit, Department of Medicine, and.
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20240326
PL  - United States
TA  - JCI Insight
JT  - JCI insight
JID - 101676073
RN  - 0 (Fgf23 protein, mouse)
RN  - 7Q7P4S7RRE (Fibroblast Growth Factor-23)
RN  - 62031-54-3 (Fibroblast Growth Factors)
RN  - EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gq-G11)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Parathyroid Hormone)
RN  - 0 (GNA11 protein, mouse)
RN  - Hypocalciuric hypercalcemia, familial, type 1
SB  - IM
MH  - Animals
MH  - Female
MH  - Male
MH  - Mice
MH  - *Disease Models, Animal
MH  - *Fibroblast Growth Factor-23
MH  - *Fibroblast Growth Factors/blood/genetics/metabolism
MH  - *GTP-Binding Protein alpha Subunits, Gq-G11/genetics/metabolism
MH  - *Hypercalcemia/genetics/congenital/blood/metabolism
MH  - Hypophosphatemia/genetics/metabolism
MH  - Interleukin-1beta/metabolism/genetics/blood
MH  - Liver/metabolism
MH  - *Mice, Knockout
MH  - Parathyroid Hormone/blood/metabolism
MH  - Signal Transduction
OTO - NOTNLM
OT  - Endocrinology
OT  - G proteins
OT  - Genetic diseases
OT  - Mouse models
EDAT- 2024/03/26 18:43
MHDA- 2024/05/08 12:45
CRDT- 2024/03/26 12:04
PHST- 2024/01/03 00:00 [received]
PHST- 2024/03/14 00:00 [accepted]
PHST- 2024/05/08 12:45 [medline]
PHST- 2024/03/26 18:43 [pubmed]
PHST- 2024/03/26 12:04 [entrez]
AID - 178993 [pii]
AID - 10.1172/jci.insight.178993 [doi]
PST - epublish
SO  - JCI Insight. 2024 Mar 26;9(9):e178993. doi: 10.1172/jci.insight.178993.