SFEBES2022 Oral Communications Bone and Calcium (6 abstracts)
Hypercalcaemic mice harbouring a germline ablation of G-protein subunit alpha-11 have anaemia that is corrected by treatment with erythropoietin
Fadil Hannan 1 , Mark Stevenson 1 , Kreepa Kooblall 1 , Mie Olesen 1 , Marianne Yon 2 , Michelle Stewart 2 , Sara Wells 2 , J.H. Duncan Bassett 3 , Graham Williams 3 & Rajesh Thakker 1
1University of Oxford, Oxford, United Kingdom; 2MRC Harwell, Oxfordshire, United Kingdom; 3Imperial College London, London, United Kingdom
G-protein subunit α-11 (Gα11), which is encoded by GNA11, plays a major role in calcium homeostasis by regulating parathyroid hormone (PTH) secretion, and germline loss-of-function mutations cause familial hypocalciuric hypercalcaemia type 2 (FHH2). Since Gα11 is ubiquitously expressed, we investigated whether FHH2 is associated with additional non-calcitropic phenotypes by analysing mice harbouring a homozygous germline deletion of Gna11 (Gna11-/-). Studies were conducted in male and female mice aged 16-28 weeks in accordance with institutional welfare guidelines. Gna11-/- mice had significantly reduced body weight and viability. The proportion of viable Gna11-/- mice was ~25% less than expected from a Mendelian pattern of inheritance (P=0.01). Biochemical analysis showed that Gna11-/- mice were hypercalcaemic compared to wild-type (WT) mice (plasma adjusted-calcium = 2.70±0.02 mM vs. 2.33±0.01 mM, P<0.0001), and hypercalcaemia was associated with significant increases in plasma PTH and 24-hour urine calcium excretion. Further detailed phenotyping demonstrated that Gna11-/- mice had reduced haemoglobin (13.3±0.1 g/dL vs. 14.5±0.1 g/dL, P<0.0001) and haematocrit compared to WT animals. The anaemia was not associated with altered serum iron or ferritin. Moreover, bone marrow histology did not detect fibrosis or reduced cellularity. Importantly, the haemoglobin values were negatively correlated with plasma adjusted-calcium (r=-0.73, P<0.0001), indicating that the hypercalcaemia may have an underlying role in the cause of the anaemia. As extracellular calcium has previously been reported to affect renal erythropoietin secretion, we assessed whether the anaemia was due to alterations in erythropoietin. Reverse transcription-quantitative PCR and protein blotting did not reveal any alterations in erythropoietin mRNA or protein expression in Gna11-/- mouse kidneys. However, subcutaneous administration of recombinant erythropoietin (1200U/kg bolus) normalised haemoglobin and haematocrit values in Gna11-/- mice at 4-days post-treatment. In summary, these studies highlight potential roles for Gα11 and/or plasma calcium in erythropoiesis.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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