Bone biomechanical properties in LRP5 mutant mice

Akhter, Mohammed P.; Wells, Daniel; Short, S.; Cullen, D. M.; Johnson, Mark; Haynatzki, Gleb; Babij, Philip; Allen, Kristina M.; Yaworsky, Paul J.; Bex, Frederick J.; Recker, Robert R.

doi:10.1016/j.bone.2004.02.018

Cited by 140 publications

(100 citation statements)

References 26 publications

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“…The G171V mutation was found to have greater structural and material strength and tibial stiffness (26) and increased vertebral compressive and femoral bending strengths. (26) In humans clinically presenting with increased bone mass and later shown to be carriers of the T253I-Lrp5 genotype, the strength of trabecular bone was increased, (13) suggesting that biomechanical properties are changed in Lrp5-HBM patients. These biochemical properties may account for the lower prevalence of fractures observed compared to those with autosomal dominant osteopetrosis type II.…”

Section: Discussionmentioning

confidence: 95%

Levels of serotonin, sclerostin, bone turnover markers as well as bone density and microarchitecture in patients with high-bone-mass phenotype due to a mutation in Lrp5

Frost

Andersen

Gossiel

et al. 2011

Journal of Bone and Mineral Research

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Patients with an activation mutation of the Lrp5 gene exhibit high bone mass (HBM). Limited information is available regarding compartment-specific changes in bone. The relationship between the phenotype and serum serotonin is not well documented. To evaluate bone, serotonin, and bone turnover markers (BTM) in Lrp5-HBM patients, we studied 19 Lrp5-HBM patients (T253I) and 19 ageand sex-matched controls. DXA and HR-pQCT were used to assess BMD and bone structure. Serum serotonin, sclerostin, dickkopf-related protein 1 (DKK1), and BTM were evaluated. Z-scores for the forearm, total hip, lumbar spine, forearm, and whole body were significantly increased (mean AE SD) between 4.94 AE 1.45 and 7.52 AE 1.99 in cases versus À0.19 AE 1.19 to 0.58 AE 0.84 in controls. Tibial and radial cortical areas, thicknesses, and BMD were significantly higher in cases. In cases, BMD at the lumbar spine and forearm and cortical thickness were positively associated and trabecular area negatively associated with age (r ¼ 0.49, 0.57, 0.74, and À0.61, respectively, p < .05). Serotonin was lowest in cases (69.5 [29.9-110.4] ng/mL versus 119. 4 [62.3-231.0] ng/mL, p < .001) and inversely associated with tibial cortical density (r ¼ À0.49, p < .05) and directly with osteocalcin (OC), bone-specific alkaline phosphatase (B-ALP), and procollagen type 1 amino-terminal propeptide (PINP) (r ¼ 0.52-0.65, p < .05) in controls only. OC and S-CTX were lower and sclerostin higher in cases, whereas B-ALP, PINP, tartrate-resistant acid phosphatase (TRAP), and dickkopf-related protein 1 (DKK1) were similar in cases and controls. In conclusion, increased bone mass in Lrp5-HBM patients seems to be caused primarily by changes in trabecular and cortical bone mass and structure. The phenotype appeared to progress with age, but BTM did not suggest increased bone formation. ß

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Section: Discussionmentioning

confidence: 95%

Levels of serotonin, sclerostin, bone turnover markers as well as bone density and microarchitecture in patients with high-bone-mass phenotype due to a mutation in Lrp5

Frost

Andersen

Gossiel

et al. 2011

Journal of Bone and Mineral Research

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“…Some affected family members also have torus platinus phenotype [58]. A corresponding gain-of-function mouse model was generated, which bears the G171V mutation ascribed to human high bone mass phenotype [60,61]. The Lrp5 G171 mice have increased bone mineral density(BMD) as a result of constitutively active receptor function.…”

Section: Lrp5mentioning

confidence: 99%

Wnt signaling and skeletal development

Liu

Kohlmeier

Wang

2008

Cellular Signalling

134

103

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Wnt proteins are a family of secreted proteins that regulate many aspects of cellular functions. The discovery that mutations in low-density lipoprotein receptor-related protein 5, a putative Wnt coreceptor, could positively and negatively affect bone mass in humans generated an enormous amount of interest in the possible role of the Wnt signaling pathway in skeletal biology. Over the last decade, considerable progress has been made in determining the role of the canonical Wnt signaling pathway in various aspects of skeletal development. Furthermore, recent evidence indicates the important role of non-canonical Wnt signaling in skeletal development. In this review we discuss the current understanding of the role of Wnt signaling in chondrogenesis, osteoblastogenesis, and osteoclastogenesis.

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“…The converse is found in patients with dominant "gain-of-function" mutations in LRP5 which exhibit abnormally high bone density [7,8]. A transgenic mouse model carrying a human LRP5 high bone mass mutation exhibited significant increases in bone density and mechanical properties [9,10]. Studies have shown that removing one Lrp6 copy from Lrp5 −/− mice increases the osteoporosis severity, suggesting that both LRP5 and LRP6 are critical determinants of bone mass [11].…”

Section: Introductionmentioning

confidence: 99%

Bone mass is inversely proportional to Dkk1 levels in mice

MacDonald

Joiner

Oyserman

et al. 2007

Bone

156

106

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The Wnt/β-catenin signaling pathway has emerged as a key regulator in bone development and bone homeostasis. Loss-of-function mutations in the Wnt co-receptor LRP5 result in osteoporosis and "activating" mutations in LRP5 result in high bone mass. Dickkopf-1 (DKK1) is a secreted Wnt inhibitor that binds LRP5 and LRP6 during embryonic development, therefore it is expected that a decrease in DKK1 will result in an increase in Wnt activity and a high bone mass phenotype. Dkk1 −/− knockout mice are embryonic lethal, but mice with hypomorphic Dkk1 d (doubleridge) alleles that express low amounts of Dkk1 are viable. In this study we generated an allelic series by crossing Dkk1 +/− and Dkk1 +/d mice resulting in the following genotypes with decreasing Dkk1 expression levels: +/+, +/d, +/− and d/−. Using μCT imaging we scanned dissected left femora and calvariae from eight week old mice (n=60). We analyzed the distal femur to represent trabecular bone and the femur diaphysis for cortical endochondral bone. A region of the parietal bones was used to analyze intramembranous bone of the calvaria. We found that trabecular bone volume is increased in Dkk1 mutant mice in a manner that is inversely proportional to the level of Dkk1 expression. Trabeculae number and thickness were significantly higher in the low Dkk1 expressing genotypes from both female and male mice. Similar results were found in cortical bone with an increase in cortical thickness and cross sectional area of the femur diaphysis that correlated with lower Dkk1 expression. No consistent differences were found in the calvaria measurements. Our results indicate that the progressive Dkk1 reduction increases trabecular and cortical bone mass and that even a 25% reduction in Dkk1 expression could produce significant increases in trabecular bone volume fraction. Thus DKK1 is a negative regulator of normal bone homeostasis in vivo. Our study suggests that manipulation of DKK1 function or expression may have therapeutic significance for the treatment of low bone mass disorders.

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Bone biomechanical properties in LRP5 mutant mice

Cited by 140 publications

References 26 publications

Levels of serotonin, sclerostin, bone turnover markers as well as bone density and microarchitecture in patients with high-bone-mass phenotype due to a mutation in Lrp5

Levels of serotonin, sclerostin, bone turnover markers as well as bone density and microarchitecture in patients with high-bone-mass phenotype due to a mutation in Lrp5

Wnt signaling and skeletal development

Bone mass is inversely proportional to Dkk1 levels in mice

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