Histologic evidence for osteopenia and increased bone turnover in ovariectomized rats

Wronski, Thomas J.; Walsh, C. C.; Ignaszewski, L. A.

doi:10.1016/8756-3282(86)90683-6

Cited by 296 publications

(141 citation statements)

References 11 publications

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“…In females, the loss of trabecular bone volume following ovariectomy was associated with increased osteoclast and mineralizing surface (MS), consistent with the characteristic response to estrogen deficiency (11)(12)(13)(14). The increased osteoclast surface in wild-type and Y2 Ϫ/Ϫ mice was comparable and not affected by Y2 receptor deletion (Fig.…”

Section: Germ Line Y2 Receptor Deletion and Gonadectomy-induced Bone supporting

confidence: 66%

Conditional Deletion of Hypothalamic Y2 Receptors Reverts Gonadectomy-induced Bone Loss in Adult Mice

Allison

Baldock

Sainsbury

et al. 2006

Journal of Biological Chemistry

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Reduction in levels of sex hormones at menopause in women is associated with two common, major outcomes, the accumulation of white adipose tissue, and the progressive loss of bone because of excess osteoclastic bone resorption exceeding osteoblastic bone formation. Current antiresorptive therapies can reduce osteoclastic activity but have only limited capacity to stimulate osteoblastic bone formation and restore lost skeletal mass. Likewise, the availability of effective pharmacological weight loss treatments is currently limited. Here we demonstrate that conditional deletion of hypothalamic neuropeptide Y2 receptors can prevent ongoing bone loss in sex hormonedeficient adult male and female mice. This benefit is attributable solely to activation of an anabolic osteoblastic bone formation response that counterbalances persistent elevation of bone resorption, suggesting the Y2-mediated anabolic pathway to be independent of sex hormones. Furthermore, the increase in fat mass that typically occurs after ovariectomy is prevented by germ line deletion of Y2 receptors, whereas in male mice body weight and fat mass were consistently lower than wild-type regardless of sex hormone status. Therefore, this study indicates a role for Y2 receptors in the accumulation of adipose tissue in the hypogonadal state and demonstrates that hypothalamic Y2 receptors constitutively restrain osteoblastic activity even in the absence of sex hormones. The increase in bone formation after release of this tonic inhibition suggests a promising new avenue for osteoporosis treatment.With age, changes in endocrine function can significantly affect physiological processes often with detrimental effects on health. One of the most substantial changes occurs with menopause in women, with cessation of estrogen production by the ovaries. This abrupt and dramatic decrease in estrogen production results in a number of acute and long term physiological effects, among the most notable of these being the loss of bone leading to the development of osteoporosis and increased deposition of white adipose tissue, contributing to an increased risk of heart disease and associated complications.In the adult skeleton, bone mass and strength are determined by the multicellular process of bone remodeling, in which osteoclastic bone resorption is followed by osteoblastic bone formation. This turnover process is normally tightly coupled, such that the amount of bone resorbed equals the amount of bone formed, maintaining a constant bone mass. Multiple endocrine factors regulate turnover, in particular the sex hormones estrogen and testosterone, which protect bone by exerting anti-apoptotic effects on osteoblasts and pro-apoptotic effects on osteoclasts, in addition to suppressing osteoclast activity through both direct and indirect mechanisms (1, 2). Loss of sex hormones following menopause in women or in hypogonadal males results in increased osteoclast activity and loss of bone mass. Most current osteoporosis treatments inhibit bone resorption; however, although thes...

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Section: Germ Line Y2 Receptor Deletion and Gonadectomy-induced Bone supporting

confidence: 66%

Conditional Deletion of Hypothalamic Y2 Receptors Reverts Gonadectomy-induced Bone Loss in Adult Mice

Allison

Baldock

Sainsbury

et al. 2006

Journal of Biological Chemistry

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“…Rats also have advantages over mice for these tests because of their larger bone size, allowing more precise structural and biomechanical measurements. Importantly, rats have proven to be a highly predictive animal model of fracture risk in humans [1]. Our previous work has allowed us to identify several inbred rats strains that are similar in body weight but vary considerably in bone strength and structure and therefore are ideal for the identification of genes contributing to the variation in these two traits.…”

Section: Introductionmentioning

confidence: 99%

Genetic loci affecting bone structure and strength in inbred COP and DA rats

Sun

Alam

Liu

et al. 2008

Bone

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Previous studies have shown that the Copenhagen 2331 (COP) and Dark Agouti (DA) rats have significant differences in bone structure and strength despite their similar body mass. Thus, these inbred rat strains may provide a unique resource to identify the genetics underlying the phenotypic variation in bone fragility. A sample of 828 (405 males and 423 females) COP × DA F2 progeny had extensive phenotyping for bone structure measures including cortical bone area and polar moment of inertia at the femur midshaft and total, cortical and trabecular bone areas, for the lumbar vertebra 5 (L5). Bone strength phenotypes included ultimate force, stiffness and work to failure of femur and L5. These skeletal phenotypes were measured using peripheral quantitative computed tomography (pQCT) and mechanical testing. A whole-genome screen was conducted in the F2 rats, using microsatellite markers spaced at approximately 20 cM intervals. Genetic marker maps were generated from the F2 data and used for genome-wide linkage analyses to detect linkage to the bone structure and strength phenotypes. Permutation testing was employed to obtain the thresholds for genomewide significance (p<0.01). Significant QTL for femur structure and strength were identified on chromosome (Chr) 1 with a maximum LOD score of 33.5; evidence of linkage was found in both the male and female rats. In addition, Chrs 6, 7, 10, 13, 15 and 18 were linked to femur midshaft structure. QTL linked to femur strength were identified on Chrs 5 and 10. For L5 vertebrae, Chrs 2, 16, and 18 harbored QTL for cortical structure and trabecular structure for L5 was linked to Chrs 1, 7, 12, and 18. One female-specific QTL for femur ultimate force was identified on Chr 5, and two male-specific QTL for L5 cortical area were found on Chrs 2 and 18. Our study demonstrates strong evidence of linkage for bone structure and strength to multiple rat chromosomes.

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“…Alguns autores relatam maior redução da quantidade de osso na tíbia do que nas vértebras lombares (44), e acometendo somente o tecido ósseo trabecular (45). No entanto, embora a osteopenia tenha sido mais intensa no tecido ósseo trabecular, sabidamente de maior metabolismo, já haviam indícios dos efeitos da deficiência dos esteróides sexuais sobre a cortical dos ossos longos e das vértebras.…”

Section: Grupo Eutireóideo Castradounclassified

Efeito da associação hipotireoidismo-castração no osso e nas paratireóides de ratas adultas

Ribeiro

Serákides

Ocarino

et al. 2004

Arq Bras Endocrinol Metab

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RESUMOO efeito do hipotireoidismo sobre o metabolismo ósseo e as paratireóides na deficiência ou suficiência dos esteróides ovarianos foi estudado em 32 ratas Wistar, com 2 meses de idade, distribuídas em 4 grupos de 8: eutireóideo não castrado (ENC), eutireóideo castrado (EC), hipotireóideo não castrado (HNC) e hipotireóideo castrado (HC). Após 120 dias de tratamento, as ratas foram sacrificadas e o plasma colhido para dosagem de T4 livre. Foi evidenciada hipertrofia das paratireóides somente no grupo HNC. As ratas do grupo HNC apresentaram osteopenia de maior extensão e intensidade, decorrente do menor crescimento, da inibição da aposição e do aumento da reabsorção ósseas. Nas ratas EC, a osteopenia foi causada por menor aposição e aumento da reabsorção ósseas. Embora a osteopenia na associação hipotireoidismo-castração tenha sido quase sempre mais intensa em relação à das ratas EC, sua intensidade, quando comparada à osteopenia dos animais HNC, foi variável e dependente do sítio ósseo estudado. Apesar de causar necrose dos ossos de maior metabolismo, a associação hipotireoidismo-castração não potencializou a osteopenia decorrente da ação isolada do hipotireoidismo até os 120 dias de tratamento. The effect of hypothyroidism on bone metabolism and the parathyroids in states of deficiency or sufficiency of sex steroids was studied in 32 two-months-old female Wistar rats distributed in 4 groups of 8 animals each: intact euthyroid (IE), castrated euthyroid (CE), intact hypothyroid (IH) and castrated hypothyroid (CH). After 120 days of treatment, animals were sacrificed and plasma taken to assess free T4. Hyperplasia or hypertrophy of all parathyroids were evident only in IH and CE groups. Of all groups, IH rats presented the most extensive osteopenia, reaching lumbar vertebrae, dental alveolae (jaw and mandible) and long bones. In this group osteopenia resulted from the reduced bone growth, inhibition of bone apposition and return of bone resorption. Although osteopenia in the CH group was almost always more intense in relation to osteopenia presented by CE rats, its intensity was variable when compared to IH rats and dependent on the region studied. Even though it also caused necrosis of higher metabolism bones, the association hypothyroidism-castration did not potentialize the resultant osteopenia of the isolated action of hypothyroidism or castration until 120 days of treatment.

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Histologic evidence for osteopenia and increased bone turnover in ovariectomized rats

Cited by 296 publications

References 11 publications

Conditional Deletion of Hypothalamic Y2 Receptors Reverts Gonadectomy-induced Bone Loss in Adult Mice

Conditional Deletion of Hypothalamic Y2 Receptors Reverts Gonadectomy-induced Bone Loss in Adult Mice

Genetic loci affecting bone structure and strength in inbred COP and DA rats

Efeito da associação hipotireoidismo-castração no osso e nas paratireóides de ratas adultas

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