An ENU-induced mutation in the Ankrd11 gene results in an osteopenia-like phenotype in the mouse mutant Yoda

2008 ◽  
Vol 32 (3) ◽  
pp. 311-321 ◽  
Author(s):  
Ivana Barbaric ◽  
Mark J. Perry ◽  
T. Neil Dear ◽  
Alexandra Rodrigues Da Costa ◽  
Daniela Salopek ◽  
...  
Keyword(s):  
Bone Mass ◽  
Positional Cloning ◽  
Genetic Basis ◽  
Bone Homeostasis ◽  
Mouse Mutant ◽  
Mineral Density ◽  
Enu Mutagenesis ◽  
Repeat Domain ◽  
Ankyrin Repeat Domain ◽  
Genetic Regulator

The mechanisms that regulate bone mass are important in a variety of complex diseases such as osteopenia and osteoporosis. Regulation of bone mass is a polygenic trait and is also influenced by various environmental and lifestyle factors, making analysis of the genetic basis difficult. As an effort toward identifying novel genes involved in regulation of bone mass, N-ethyl- N-nitrosourea (ENU) mutagenesis in mice has been utilized. Here we describe a mouse mutant termed Yoda that was identified in an ENU mutagenesis screen for dominantly acting mutations. Mice heterozygous for the Yoda mutation exhibit craniofacial abnormalities: shortened snouts, wider skulls, and deformed nasal bones, underlined by altered morphology of frontonasal sutures and failure of interfrontal suture to close. A major feature of the mutant is reduced bone mineral density. Homozygosity for the mutation results in embryonic lethality. Positional cloning of the locus identified a missense mutation in a highly conserved region of the ankyrin repeat domain 11 gene ( Ankrd11). This gene has not been previously associated with bone metabolism and, thus, identifies a novel genetic regulator of bone homeostasis.

scholarly journals Porcupine inhibitors impair trabecular and cortical bone mass and strength in mice

2018 ◽  
Vol 238 (1) ◽  
pp. 13-23 ◽  
Author(s):  
Thomas Funck-Brentano ◽  
Karin H Nilsson ◽  
Robert Brommage ◽  
Petra Henning ◽  
Ulf H Lerner ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Cortical Bone ◽  
Bone Strength ◽  
Bending Test ◽  
Bone Homeostasis ◽  
Mineral Density

WNT signaling is involved in the tumorigenesis of various cancers and regulates bone homeostasis. Palmitoleoylation of WNTs by Porcupine is required for WNT activity. Porcupine inhibitors are under development for cancer therapy. As the possible side effects of Porcupine inhibitors on bone health are unknown, we determined their effects on bone mass and strength. Twelve-week-old C57BL/6N female mice were treated by the Porcupine inhibitors LGK974 (low dose = 3 mg/kg/day; high dose = 6 mg/kg/day) or Wnt-C59 (10 mg/kg/day) or vehicle for 3 weeks. Bone parameters were assessed by serum biomarkers, dual-energy X-ray absorptiometry, µCT and histomorphometry. Bone strength was measured by the 3-point bending test. The Porcupine inhibitors were well tolerated demonstrated by normal body weight. Both doses of LGK974 and Wnt-C59 reduced total body bone mineral density compared with vehicle treatment (P < 0.001). Cortical thickness of the femur shaft (P < 0.001) and trabecular bone volume fraction in the vertebral body (P < 0.001) were reduced by treatment with LGK974 or Wnt-C59. Porcupine inhibition reduced bone strength in the tibia (P < 0.05). The cortical bone loss was the result of impaired periosteal bone formation and increased endocortical bone resorption and the trabecular bone loss was caused by reduced trabecular bone formation and increased bone resorption. Porcupine inhibitors exert deleterious effects on bone mass and strength caused by a combination of reduced bone formation and increased bone resorption. We suggest that cancer targeted therapies using Porcupine inhibitors may increase the risk of fractures.

scholarly journals Inhibin A Is an Endocrine Stimulator of Bone Mass and Strength

Endocrinology ◽  
2007 ◽  
Vol 148 (4) ◽  
pp. 1654-1665 ◽  
Author(s):  
Daniel S. Perrien ◽  
Nisreen S. Akel ◽  
Paul K. Edwards ◽  
Adam A. Carver ◽  
Manali S. Bendre ◽  
...  
Keyword(s):  
Bone Mass ◽  
Sex Steroids ◽  
Proximal Tibia ◽  
Bone Volume ◽  
Appendicular Skeleton ◽  
Bone Homeostasis ◽  
Mineral Density ◽  
Inhibin A ◽  
Bone Cell Differentiation

Gonadal function plays a major role in bone homeostasis. It is widely held that the skeletal consequences of hypogonadism are solely due to a loss of sex steroids; however, increases in bone turnover begin during perimenopause before decreases in serum estradiol levels. These data and our demonstration that inhibins acutely regulate bone cell differentiation in vitro led us to test whether inhibin A (InhA) regulates bone mass in vivo. Using a transgenic model of inducible human InhA expression, InhA increased total body bone mineral density, increased bone volume, and improved biomechanical properties at the proximal tibia in intact mice and also prevented the loss of BMD and bone volume and strength associated with gonadectomy at both the spine and proximal tibia. In addition, InhA increased mineral apposition rate, double-labeled surface, and serum osteocalcin levels in vivo and osteoblastogenesis ex vivo without affecting osteoclast number or activity. Together these results demonstrate novel stimulatory effects of InhA on the skeleton in vivo. These studies provide in vivo evidence demonstrating that gonadal factors other than sex steroids play an important role in regulating bone mass and strength and, combined with our previous clinical data, suggest that gonadal InhA may be a component of the normal endocrine repertoire that regulates bone quality in both the axial and appendicular skeleton.

Calcium and Vitamin D Supplementation. Myths and Realities with Regard to Cardiovascular Risk

2019 ◽  
Vol 17 (6) ◽  
pp. 610-617 ◽  
Author(s):  
Giovanna Muscogiuri ◽  
Luigi Barrea ◽  
Barbara Altieri ◽  
Carolina Di Somma ◽  
Harjit pal Bhattoa ◽  
...  
Keyword(s):  
Vitamin D ◽  
Side Effects ◽  
Secondary Hyperparathyroidism ◽  
Calcium Supplementation ◽  
Physiological Role ◽  
Bone Diseases ◽  
Current Evidence ◽  
Bone Homeostasis ◽  
Mineral Density ◽  
Muscle Health

Vitamin D and calcium are considered crucial for the treatment of bone diseases. Both vitamin D and calcium contribute to bone homeostasis but also preserve muscle health by reducing the risk of falls and fractures. Low vitamin D concentrations result in secondary hyperparathyroidism and contribute to bone loss, although the development of secondary hyperparathyroidism varies, even in patients with severe vitamin D deficiency. Findings from observational studies have shown controversial results regarding the association between bone mineral density and vitamin D/calcium status, thus sparking a debate regarding optimum concentrations of 25-hydroxyvitamin D and calcium for the best possible skeletal health. Although most of the intervention studies reported a positive effect of supplementation with calcium and vitamin D on bone in patients with osteoporosis, this therapeutic approach has been a matter of debate regarding potential side effects on the cardiovascular (CV) system. Thus, the aim of this review is to consider the current evidence on the physiological role of vitamin D and calcium on bone and muscle health. Moreover, we provide an overview on observational and interventional studies that investigate the effect of vitamin D and calcium supplementation on bone health, also taking into account the possible CV side-effects. We also provide molecular insights on the effect of calcium plus vitamin D on the CV system.

scholarly journals Asparaginyl Hydroxylation of the Notch Ankyrin Repeat Domain by Factor Inhibiting Hypoxia-inducible Factor

2007 ◽  
Vol 282 (33) ◽  
pp. 24027-24038 ◽  
Author(s):  
Mathew L. Coleman ◽  
Michael A. McDonough ◽  
Kirsty S. Hewitson ◽  
Charlotte Coles ◽  
Jasmin Mecinović ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Ankyrin Repeat ◽  
Repeat Domain ◽  
Ankyrin Repeat Domain

scholarly journals The Association between Bone Mineral Density and Periodontal Disease in Middle-Aged Adults

2021 ◽  
Vol 18 (6) ◽  
pp. 3321
Author(s):  
Hsin-Hua Chou ◽  
Sao-Lun Lu ◽  
Sen-Te Wang ◽  
Ting-Hsuan Huang ◽  
Sam Li-Sheng Chen
Keyword(s):  
Bone Mineral Density ◽  
Young Adults ◽  
Bone Mass ◽  
Periodontal Disease ◽  
Bone Mineral ◽  
Intervention Program ◽  
Past History ◽  
Low Bone Mass ◽  
Mineral Density ◽  
Periodontal Index

The association between osteoporosis and periodontal disease (PD) has been revealed by previous studies, but there have been few studies on the association in younger adults. We enrolled a total of 7298 adults aged 40 to 44 who underwent PD screening between 2003 and 2008. Data on quantitative ultrasound for the measurement of bone mineral density (BMD) were collected for the diagnostic criteria of osteopenia and osteoporosis. The Community Periodontal Index (CPI) was measured for defining PD. A multiple logistic regression model was used to assess the effect of low bone mass on the risk of PD. Of 7298 enrollees, 31% had periodontal pockets >3 mm, 36.2% had osteopenia, and 2.1% had osteoporosis. The 39.8% of PD prevalence was high in adults with osteoporosis, followed by 33.3% in osteopenia. A negative association was found between BMD and CPI value (p < 0.0001). Low bone mass was associated with the risk of PD (adjusted OR: 1.13; 95% CI:1.02–1.26) after adjusting the confounding factors, including age, gender, education level, overweight, smoking status, past history of osteoporosis, and diabetes mellitus. An association between BMD and PD among young adults was found. An intervention program for the prevention of PD and osteoporosis could be considered starting in young adults.

scholarly journals Osteoarthritis: Insights Offered by the Study of Bone Mass Genetics

2021 ◽  
Vol 19 (2) ◽  
pp. 115-122
Author(s):  
A. Hartley ◽  
C. L. Gregson ◽  
L. Paternoster ◽  
J. H. Tobias
Keyword(s):  
Bone Mass ◽  
Causal Effect ◽  
Mendelian Randomisation ◽  
Mineral Density ◽  
High Bone Mass ◽  
Increased Risk ◽  
High Bone ◽  
Genetic Mechanisms ◽  
Additional Support

Abstract Purpose of Review This paper reviews how bone genetics has contributed to our understanding of the pathogenesis of osteoarthritis. As well as identifying specific genetic mechanisms involved in osteoporosis which also contribute to osteoarthritis, we review whether bone mineral density (BMD) plays a causal role in OA development. Recent Findings We examined whether those genetically predisposed to elevated BMD are at increased risk of developing OA, using our high bone mass (HBM) cohort. HBM individuals were found to have a greater prevalence of OA compared with family controls and greater development of radiographic features of OA over 8 years, with predominantly osteophytic OA. Initial Mendelian randomisation analysis provided additional support for a causal effect of increased BMD on increased OA risk. In contrast, more recent investigation estimates this relationship to be bi-directional. However, both these findings could be explained instead by shared biological pathways. Summary Pathways which contribute to BMD appear to play an important role in OA development, likely reflecting shared common mechanisms as opposed to a causal effect of raised BMD on OA. Studies in HBM individuals suggest this reflects an important role of mechanisms involved in bone formation in OA development; however further work is required to establish whether the same applies to more common forms of OA within the general population.

scholarly journals Increased development of radiographic hip osteoarthritis in individuals with high bone mass: a prospective cohort study

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
April Hartley ◽  
Sarah A. Hardcastle ◽  
Monika Frysz ◽  
Jon Parkinson ◽  
Lavinia Paternoster ◽  
...  
Keyword(s):  
Bone Mass ◽  
Functional Limitations ◽  
Functional Limitation ◽  
Hip Osteoarthritis ◽  
Joint Space ◽  
Mineral Density ◽  
High Bone Mass ◽  
High Bone ◽  
Subchondral Sclerosis

Abstract Background Individuals with high bone mass (HBM) have a greater odds of prevalent radiographic hip osteoarthritis (OA), reflecting an association with bone-forming OA sub-phenotypes (e.g. osteophytosis, subchondral sclerosis). As the role of bone mineral density (BMD) in hip OA progression is unclear, we aimed to determine if individuals with HBM have increased incidence and/or progression of bone-forming OA sub-phenotypes. Methods We analysed an adult cohort with and without HBM (L1 and/or total hip BMD Z-score > + 3.2) with pelvic radiographs collected at baseline and 8-year follow-up. Sub-phenotypes were graded using the OARSI atlas. Superior/inferior acetabular/femoral osteophyte and medial/superior joint space narrowing (JSN) grades were summed and Δosteophyte and ΔJSN derived. Pain and functional limitations were quantified using the WOMAC questionnaire. Associations between HBM status and change in OA sub-phenotypes were determined using multivariable linear/logistic regression, adjusting for age, sex, height, total body fat mass, follow-up time and baseline sub-phenotype grade. Generalised estimating equations accounted for individual-level clustering. Results Of 136 individuals, 62% had HBM at baseline, 72% were female and mean (SD) age was 59 (10) years. HBM was positively associated with both Δosteophytes and ΔJSN (adjusted mean grade differences between individuals with and without HBM βosteophyte = 0.30 [0.01, 0.58], p = 0.019 and βJSN = 0.10 [0.01, 0.18], p = 0.019). Incident subchondral sclerosis was rare. HBM individuals had higher WOMAC hip functional limitation scores (β = 8.3 [0.7, 15.98], p = 0.032). Conclusions HBM is associated with the worsening of hip osteophytes and JSN over an average of 8 years, as well as increased hip pain and functional limitation.

scholarly journals Bone and Mineral Metabolism Phenotypes in MEN1-Related and Sporadic Primary Hyperparathyroidism, before and after Parathyroidectomy

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1895
Author(s):  
Francesca Marini ◽  
Francesca Giusti ◽  
Federica Cioppi ◽  
Davide Maraghelli ◽  
Tiziana Cavalli ◽  
...  
Keyword(s):  
Primary Hyperparathyroidism ◽  
Bone Mass ◽  
Bone Metabolism ◽  
Mineral Metabolism ◽  
Parathyroid Tissue ◽  
Young Patients ◽  
Surgical Removal ◽  
Mineral Density ◽  
Bone Mass Loss ◽  
Before And After

Primary hyperparathyroidism (PHPT) is the most common endocrinopathy in multiple endocrine neoplasia type 1 (MEN1). Persistent levels of increased parathyroid hormone (PTH) result in a higher incidence of osteopenia and osteoporosis compared to the general population. Surgical removal of hyper-functioning parathyroid tissue is the therapy of choice. This retrospective study evaluated the effect of parathyroidectomy (PTX) on bone metabolism and bone mass in two series of patients with MEN1 PHPT and sporadic PHPT (sPHPT) by comparing bone metabolism-related biochemical markers and bone mineral density (BMD) before and after surgery. Our data confirmed, in a higher number of cases than in previously published studies, the efficacy of PTX, not only to rapidly restore normal levels of PTH and calcium, but also to normalize biochemical parameters of bone resorption and bone formation, and to improve spine and femur bone mass, in both MEN1 PHPT and sPHPT. Evaluation of single-patient BMD changes after surgery indicates an individual variable bone mass improvement in a great majority of MEN1 PHPT patients. In MEN1 patients, PTX is strongly suggested in the presence of increased PTH and hypercalcemia to prevent/reduce the early-onset bone mass loss and grant, in young patients, the achievement of the bone mass peak; routine monitoring of bone metabolism and bone mass should start from adolescence. Therapy with anti-fracture drugs is indicated in MEN1 patients with BMD lower than the age-matched normal values.

Disease Damage Accrual and Low Bone Mineral Density in Female Patients with Systemic Lupus Erythematosus

2021 ◽  
pp. 109980042110055
Author(s):  
María Correa-Rodríguez ◽  
Gabriela Pocovi-Gerardino ◽  
José-Luis Callejas-Rubio ◽  
Raquel Ríos-Fernández ◽  
Blanca Rueda-Medina ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Systemic Lupus Erythematosus ◽  
Lumbar Spine ◽  
Bone Mass ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Mineral Density ◽  
Systemic Lupus ◽  
Damage Accrual ◽  
Disease Damage

Osteoporosis is a common comorbidity in patients with systemic lupus erythematosus (SLE), but the potential contribution of disease-associated factors to bone status in SLE is not well known because the reported risk factors from different studies differ greatly. We aimed to examine frequency of reduced bone mass in women with SLE, and determine their potential associations with disease activity, damage accrual and SLE-related clinical markers. A cross-sectional study including 121 Caucasian pre-menopausal and postmenopausal women was conducted (mean age 49.2 ± 12.4 years). The SLE Disease Activity Index (SLEDAI-2 K) and the SDI Damage Index were used to assess disease activity and disease-related damage, respectively. Bone mineral density (BMD) of the left femoral neck and lumbar spine (L2–L4) were measured by dual-energy X-ray absorptiometry. Ten patients (8.3%) had osteoporosis, 63 (52.1%) patients had osteopenia and 6.8% of women had history of previous fracture. Patients with low bone mass had a significantly higher mean SDI (1.3 ± 1.2 versus 0.7 ± 1.0 p = 0.003). T-score at lumbar spine was inversely correlated with SDI score (r = -0.222, p = 0.014) and complement C3 level ( r = −0.206, p = .024). SDI scores were significantly different between patients with osteoporosis, osteopenia, and normal BMD after adjusting for covariates ( p = .004). There is a high prevalence of low BMD in Caucasian women with SLE, and this status was associated with higher damage accrual scores, supporting that disease damage may itself be a major contributor to the low BMD. Women with SLE with organ damage require regular bone status monitoring to prevent further musculoskeletal damage.

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