Vitamin B12–dependent taurine synthesis regulates growth and bone mass
Pablo Roman-Garcia, Isabel Quiros-Gonzalez, Lynda Mottram, Liesbet Lieben, Kunal Sharan, Arporn Wangwiwatsin, Jose Tubio, Kirsty Lewis, Debbie Wilkinson, Balaji Santhanam, Nazan Sarper, Simon Clare, George S. Vassiliou, Vidya R. Velagapudi, Gordon Dougan, Vijay K. Yadav
Pablo Roman-Garcia, Isabel Quiros-Gonzalez, Lynda Mottram, Liesbet Lieben, Kunal Sharan, Arporn Wangwiwatsin, Jose Tubio, Kirsty Lewis, Debbie Wilkinson, Balaji Santhanam, Nazan Sarper, Simon Clare, George S. Vassiliou, Vidya R. Velagapudi, Gordon Dougan, Vijay K. Yadav
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Research Article Bone biology

Vitamin B12–dependent taurine synthesis regulates growth and bone mass

Abstract

Both maternal and offspring-derived factors contribute to lifelong growth and bone mass accrual, although the specific role of maternal deficiencies in the growth and bone mass of offspring is poorly understood. In the present study, we have shown that vitamin B12 (B12) deficiency in a murine genetic model results in severe postweaning growth retardation and osteoporosis, and the severity and time of onset of this phenotype in the offspring depends on the maternal genotype. Using integrated physiological and metabolomic analysis, we determined that B12 deficiency in the offspring decreases liver taurine production and associates with abrogation of a growth hormone/insulin-like growth factor 1 (GH/IGF1) axis. Taurine increased GH-dependent IGF1 synthesis in the liver, which subsequently enhanced osteoblast function, and in B12-deficient offspring, oral administration of taurine rescued their growth retardation and osteoporosis phenotypes. These results identify B12 as an essential vitamin that positively regulates postweaning growth and bone formation through taurine synthesis and suggests potential therapies to increase bone mass.

Authors

Pablo Roman-Garcia, Isabel Quiros-Gonzalez, Lynda Mottram, Liesbet Lieben, Kunal Sharan, Arporn Wangwiwatsin, Jose Tubio, Kirsty Lewis, Debbie Wilkinson, Balaji Santhanam, Nazan Sarper, Simon Clare, George S. Vassiliou, Vidya R. Velagapudi, Gordon Dougan, Vijay K. Yadav

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Figure 7

Taurine increases IGF1 synthesis from liver and its action in osteoblasts to regulate bone mass.

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Taurine increases IGF1 synthesis from liver and its action in osteoblast...
(A–D) Liver samples. (A) Levels of methionine and homocysteine in WT, Gif–/–(F2)/VEH, and Gif–/–(F2)/TAU liver. (B) B12-dependent (MTR) and -independent (BHMT) methionine synthesis pathways. (C) Western blot analysis of BHMT levels in WT, Gif–/–(F2)/VEH, and Gif–/–(F2)/TAU liver. Lanes were run contiguously. U.D., undetectable. (D) Levels of betaine and dimethyl-glycine in liver of WT, Gif–/–(F2)/VEH, and Gif–/–(F2)/TAU mice. (E–G) MC3T3-E1 osteoblast cells. Changes in BrdU incorporation (E), IGF1R and ERK phosphorylation (F), and Ccnd1 expression (G) in cells treated for 24 hours with vehicle, OSI906, taurine, or taurine plus OSI906. Lanes in F were run contiguously, and blots were stripped and reprobed with IGF1R or ERK. Relative quantification of pIGF1R and pERK (normalized to IGF1R and ERK, respectively) is shown below. A representative blot from 3 different experiments is shown. (H) Growth curve analysis of WT and Gif–/–(F2)/TAU+OSI906 mice (n = 5 each). (I) Bone mass analysis (BV/TV) in the vertebra of WT and Gif–/–(F2)/TAU+OSI906 mice (n = 5 per group). (J) Gut/liver/bone endocrine axis, illustrating GH/STAT5/B12-dependent changes in serum IGF1 and taurine that regulate osteoblast proliferation and bone mass. *P < 0.05; #P < 0.01. Values are mean ± SEM. Scale bar: 500 μm. See also Supplemental Figure 7.