Low‐density lipoprotein receptor‐related protein 5 variant Q89R is associated with hypertension in Japanese females

Suwazono, Yasushi; Kobayashi, Etsuko; Uetani, Mirei; Miura, Katsuyuki; Morikawa, Yuko; Ishizaki, Masao; Kido, Teruhiko; Nakagawa, Hideaki; Nogawa, Kôji

doi:10.1080/08037050600650191

Cited by 10 publications

(8 citation statements)

References 37 publications

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“…In humans, polymorphisms in LRP5 exhibit genetic linkage with elevated LDL cholesterol levels, hypertension, increased body mass index, and obesity (32,(58)(59)(60). In our studies, mice lacking Lrp5 in osteoblasts and osteocytes exhibited an age-related increase in fat mass and reductions in both lean mass and bone mass.…”

Section: Discussionsupporting

confidence: 53%

Wnt-Lrp5 Signaling Regulates Fatty Acid Metabolism in the Osteoblast

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Ellis

et al. 2015

Molecular and Cellular Biology

131

104

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fThe Wnt coreceptors Lrp5 and Lrp6 are essential for normal postnatal bone accrual and osteoblast function. In this study, we identify a previously unrecognized skeletal function unique to Lrp5 that enables osteoblasts to oxidize fatty acids. Mice lacking the Lrp5 coreceptor specifically in osteoblasts and osteocytes exhibit the expected reductions in postnatal bone mass but also exhibit an increase in body fat with corresponding reductions in energy expenditure. Conversely, mice expressing a high bone mass mutant Lrp5 allele are leaner with reduced plasma triglyceride and free fatty acid levels. In this context, Wnt-initiated signals downstream of Lrp5, but not the closely related Lrp6 coreceptor, regulate the activation of ␤-catenin and thereby induce the expression of key enzymes required for fatty acid ␤-oxidation. These results suggest that Wnt-Lrp5 signaling regulates basic cellular activities beyond those associated with fate specification and differentiation in bone and that the skeleton influences global energy homeostasis via mechanisms independent of osteocalcin and glucose metabolism. Wnt signaling regulates nearly all aspects of osteoblast function, from initial fate specification (1) to the control of osteoclast differentiation (2). In this pathway, low-density-lipoprotein (LDL)-related receptor 5 (Lrp5) and the closely related Lrp6 participate in the stabilization and activation of the transcription factor ␤-catenin by facilitating the interaction of Wnt ligands with frizzled receptors (3, 4). Osteoblasts express all the components of the Wnt/␤-catenin pathway, and most have now been linked with bone development and maintenance in humans and mouse models (5-7). Mutations in the LRP5 gene, in particular, can result in premature and generalized osteoporosis as in the rare condition osteoporosis pseudoglioma (8) or a high-bone-mass phenotype (9, 10) likely due to an increase in the number of mineralizing osteoblasts (11).Like other metabolically active cells, osteoblasts require a supply of energy-rich molecules to fuel the synthesis, deposition, and mineralization of bone matrix (12). When energy input fails to meet demand, normal bone accrual ceases, a phenomenon that is evident clinically by the arrest of longitudinal bone growth and osteopenia observed in undernourished children and adults (13, 14). Therefore, osteoblasts must possess mechanisms to acquire and regulate the utilization of fuel macromolecules, as well as the ability to communicate energy needs with other tissues.Recent studies have delineated a role for the osteoblast in a bone-pancreas endocrine loop that contributes to the regulation of glucose metabolism, as well as bone acquisition. Insulin receptor signaling in the osteoblast regulates the activity of the osteogenic transcription factor Runx2 and is required for the attainment of a mature phenotype as well as normal postnatal bone acquisition (15). In addition, insulin actions regulate the production and bioavailability of osteocalcin (15, 16), a bone-derived hormone that in ...

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Section: Discussionsupporting

confidence: 53%

Wnt-Lrp5 Signaling Regulates Fatty Acid Metabolism in the Osteoblast

Frey

Ellis

et al. 2015

Molecular and Cellular Biology

131

104

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“…This finding appears to represent another example in which key osteoblast developmental signals simultaneously alter metabolic machinery to fulfil the bioenergetic needs of differentiated osteoblast functions. The concept that Lrp5 might have a role in fuel metabolism is further supported by evidence linking polymorphisms in human LRP5 gene (A1330V, Q89R) with increased total and LDL cholesterol levels, hypertension, increased body mass index and obesity . Similarly, mice globally deficient in Lrp5 are glucose intolerant and exhibit increased plasma cholesterol levels when fed a high‐fat diet; this phenotype results from reduced clearance of chylomicron remnants from the circulation .…”

Section: Energy Substrate Utilization By Bone Cellsmentioning

confidence: 96%

Bone and the regulation of global energy balance

2015

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The skeleton, populated by large numbers of osteoblasts and long-lived osteocytes, requires a constant supply of energy-rich molecules to fuel the synthesis, deposition, and mineralization of bone matrix during bone modeling and remodeling. When these energetic demands are not met, bone acquisition is suppressed. Recent findings suggest that key developmental signals emanating from WNT- low-density lipoprotein-related receptor 5 and Hypoxia-inducible factor pathways impact osteoblast bioenergetics to accommodate the energy requirements for bone cells to fulfill their function. In vivo studies in several mutant mouse strains have confirmed a link between bone cells and global metabolism, ultimately leading to the identification of hormonal interactions between the skeleton and other tissues. The hormones insulin and leptin affect postnatal bone acquisition, while osteocalcin produced by the osteoblast in turn stimulates insulin secretion by the pancreas. These observations have prompted additional questions regarding the nature of the mechanisms of fuel sensing and processing in the osteoblast and their contribution to overall energy utilization and homeostasis. Answers to such questions should advance our understanding of metabolic diseases and may ultimately improve management of affected patients. In this review we highlight recent studies in this field and offer a perspective on the evolutionary implications of bone as a metabolic endocrine organ.

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“…13 Mice with targeted disruption of lrp5 have low bone mass and persistent embryonic eye vascularization. [17][18][19] Recently, Mani et al 20 found a mutation in the LRP5 homologue LRP6 in a family with autosomal dominant early onset coronary artery disease, metabolic syndrome and osteoporosis. 15 On normal diet, lrp5-deficient mice showed impaired glucose tolerance and glucose-induced insulin secretion.…”

Section: Introductionmentioning

confidence: 99%

“…15 In humans, LRP5 polymorphisms have been associated with obesity, 16 hypertension and hypercholesterolaemia. [17][18][19] Recently, Mani et al 20 found a mutation in the LRP5 homologue LRP6 in a family with autosomal dominant early onset coronary artery disease, metabolic syndrome and osteoporosis.…”

Section: Introductionmentioning

confidence: 99%