Reply to Lrp5 regulation of bone mass and gut serotonin synthesis

Cui, Yang; Niziolek, Paul J.; MacDonald, Bryan T.; Alenina, Natalia; Matthes, Susann; Jacobsen, Christina M.; Conlon, Ronald A.; Brommage, Robert; Powell, David R.; Bäder, Michael; Williams, Bart O.; Warman, Matthew L.; Robling, Alexander G.

doi:10.1038/nm.3697

Cited by 26 publications

(17 citation statements)

References 7 publications

(28 reference statements)

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“…These studies favor a model in which LRP5 functions occur within osteoblast lineage cells, mostly in osteocytes. There has been a public debate about these discrepancies . Therefore, the mechanisms through which LRP5 regulates bone mass need to be further investigated.…”

Section: Wnt Signaling In Aging Intestinementioning

confidence: 99%

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Wnt signaling in bone, kidney, intestine, and adipose tissue and interorgan interaction in aging

Chen

Xie

Shu

et al. 2018

Annals of the New York Academy of Sciences

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Over the last two decades, it has become increasingly apparent that Wnt signaling plays a critical role in development and adult tissue homeostasis in multiple organs and in the pathogenesis of many diseases. In particular, a crucial role for Wnt signaling in bone development and bone tissue homeostasis has been well recognized. Numerous genome-wide association studies confirmed the importance of Wnt signaling in controlling bone mass. Moreover, ample evidence suggests that Wnt signaling is essential for kidney, intestine, and adipose tissue development and homeostasis. Recent emerging evidence demonstrates that Wnt signaling may play a fundamental role in the aging process of those organs. New discoveries show that bone is not only the major reservoir for calcium and phosphate storage, but also the largest organ with multiple functions, including mineral and energy metabolism. The interactions among bone, kidney, intestine, and adipose tissue are controlled and regulated by several endocrine signals, including FGF23, klotho, sclerostin, osteocalcin, vitamin D, and leptin. Since the aging process is characterized by structural and functional decline in almost all tissues and organs, understanding the Wnt signaling-related interactions among bone, kidney, intestine, and adipose tissue in aging may shed light on the pathogenesis of age-related diseases.

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Section: Wnt Signaling In Aging Intestinementioning

confidence: 99%

“…There has been a public debate about these discrepancies. 139,140 Therefore, the mechanisms through which LRP5 regulates bone mass need to be further investigated. Of note, the intestinal tract is also one of the principal organs that control the dietary balance of calcium and phosphate so important for bone health.…”

Section: Wnt Signaling In Aging Intestinementioning

confidence: 99%

Wnt signaling in bone, kidney, intestine, and adipose tissue and interorgan interaction in aging

Chen

Xie

Shu

et al. 2018

Annals of the New York Academy of Sciences

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“… 48–50 However, this latter model has been debated. 51–54 In any event, reductions in bone mass caused by loss of Lrp5 and/or Lrp6 in the descendants of Col2-cre -expressing cells could be either owing to widespread leakiness of the Col2-cre transgene within osteoblasts or reflect significant contribution of Col2-cre expressing cells to the osteoblast lineage found in the mature skeleton.…”

Section: Discussionmentioning

confidence: 99%

Characterization of genetically engineered mouse models carrying Col2a1-cre-induced deletions of Lrp5 and/or Lrp6

et al. 2016

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Mice carrying Collagen2a1-cre-mediated deletions of Lrp5 and/or Lrp6 were created and characterized. Mice lacking either gene alone were viable and fertile with normal knee morphology. Mice in which both Lrp5 and Lrp6 were conditionally ablated via Collagen2a1-cre-mediated deletion displayed severe defects in skeletal development during embryogenesis. In addition, adult mice carrying Collagen2a1-cre-mediated deletions of Lrp5 and/or Lrp6 displayed low bone mass suggesting that the Collagen2a1-cre transgene was active in cells that subsequently differentiated into osteoblasts. In both embryonic skeletal development and establishment of adult bone mass, Lrp5 and Lrp6 carry out redundant functions.

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“…De Vernejoul and colleagues revisited the bone phenotype in mice with genetic deletion of peripheral 5HT-synthesizing enzyme tryptophan hydroxylase-1 (TPH1 -/-) and showed that osteoclasts synthesize 5HT which acts to induce osteoclast precursor differentiation in a local micro-serotoninergic system via a mechanism of RANKL-induced osteoclast formation [7]. There is controversy regarding the role of LRP5 in regulating peripheral serotonin levels and influence of peripheral serotonin on bone homeostasis [8][9][10][11][12][13][14][15][16]. Further, use of antidepressant medications, which act on serotonin system, has been shown to have impact on decreasing BMD and to increase risk for osteoporosis [17].…”

Section: Introductionmentioning

confidence: 99%

Constitutively elevated blood serotonin is associated with bone loss and type 2 diabetes in rats

Erjavec¹,

Bordukalo-Niksic²,

Grgurević³

et al. 2016

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Reduced peripheral serotonin (5HT) in mice lacking tryptophan hydroxylase (TPH1), the rate limiting enzyme for 5HT synthesis, was reported to be anabolic to the skeleton. However, in other studies TPH1 deletion either had no bone effect or an age dependent inhibition of osteoclastic bone resorption. The role of 5HT in bone therefore remains poorly understood. To address this issue, we used selective breeding to create rat sublines with constitutively high (high-5HT) and low (low-5HT) platelet 5HT level (PSL) and platelet 5HT uptake (PSU). High-5HT rats had decreased bone volume due to increased bone turnover characterized by increased bone formation and mineral apposition rate, increased osteoclast number and serum C-telopeptide level. Daily oral administration of the TPH1 inhibitor (LX1032) for 6 weeks reduced PSL and increased the trabecular bone volume and trabecular number of the spine and femur in high-5HT rats. High-5HT animals also developed a type 2 diabetes (T2D) phenotype with increased: plasma insulin, glucose, hemoglobin A1c, body weight, visceral fat, β-cell pancreatic islets size, serum cholesterol, and decreased muscle strength. Serum calcium accretion mediated by parathyroid hormone slightly increased, whereas treatment with 1,25(OH) 2 D 3 decreased PSL. Insulin reduction was paralleled by a drop in PSL in high-5HT rats. In vitro, insulin and 5HT synergistically up-regulated osteoblast differentiation isolated from high-5HT rats, whereas TPH1 inhibition decreased the number of bone marrow-derived osteoclasts. These results suggest that constitutively elevated PSL is associated with bone loss and T2D via a homeostatic interplay between the peripheral 5HT, bone and insulin.

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Reply to Lrp5 regulation of bone mass and gut serotonin synthesis

Cited by 26 publications

References 7 publications

Wnt signaling in bone, kidney, intestine, and adipose tissue and interorgan interaction in aging

Wnt signaling in bone, kidney, intestine, and adipose tissue and interorgan interaction in aging

Characterization of genetically engineered mouse models carrying Col2a1-cre-induced deletions of Lrp5 and/or Lrp6

Constitutively elevated blood serotonin is associated with bone loss and type 2 diabetes in rats

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