scholarly journals Deficiency of ATP6V1H Causes Bone Loss by Inhibiting Bone Resorption and Bone Formation through the TGF-β1 Pathway

Theranostics ◽  
2016 ◽  
Vol 6 (12) ◽  
pp. 2183-2195 ◽  
Author(s):  
Xiaohong Duan ◽  
Jin Liu ◽  
Xueni Zheng ◽  
Zhe Wang ◽  
Yanli Zhang ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Tgf Β1

An Uncoupling Agent Containing Strontium Prevents Bone Loss by Depressing Bone Resorption and Maintaining Bone Formation in Estrogen-Deficient Rats

2005 ◽  
Vol 20 (6) ◽  
pp. 1065-1074 ◽  
Author(s):  
Pierre J. Marie ◽  
Monique Hott ◽  
Dominique Modrowski ◽  
Cinderella de Pollak ◽  
Joel Guillemain ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation

scholarly journals Novel Osteogenic Factors derived from Functional Food: Role in Prevention of Osteoporosis

2015 ◽  
Vol 1 (1) ◽  
Author(s):  
Masayoshi Yamaguchi
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Functional Food ◽  
Human Subjects ◽  
Osteoclastic Bone Resorption ◽  
Bone Homeostasis ◽  
Osteoblastic Bone Formation ◽  
Prevention Of Osteoporosis ◽  
Osteogenic Effect

<p>Bone homeostasis is maintained through a delicate balance between osteoblastic bone formation and osteoclastic bone resorption. Bone loss is caused by decreasing in osteoblastic bone formation and increase in osteoclastic bone resorption, thereby leading to osteoporosis. Functional food factors may play a role in<br />the prevention of osteoporosis. Functional food factors including genistein, menaquinone-7 (vitamin K2) and β-cryptoxanthine have been shown to possess a potential osteogenic effect. These factors have been shown to reveal stimulatory effects on osteoblastic bone formation and suppressive effects on osteoclastic<br />bone resorption. Dietary intake of these factors has been shown to reveal preventive effects on bone loss in animal models of osteoporosis and human subjects. This review will introduce our findings concerning roles of functional food factors in regulation of bone homeostasis and prevention of osteoporosis.</p>

scholarly journals Free Fatty Acid Receptor 4 (GPR120) Stimulates Bone Formation and Suppresses Bone Resorption in the Presence of Elevated n-3 Fatty Acid Levels

Endocrinology ◽  
2016 ◽  
Vol 157 (7) ◽  
pp. 2621-2635 ◽  
Author(s):  
Seong Hee Ahn ◽  
Sook-Young Park ◽  
Ji-Eun Baek ◽  
Su-Youn Lee ◽  
Wook-Young Baek ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Free Fatty Acid ◽  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
High Fat Diet ◽  
Wild Type ◽  
High Fat ◽  
Free Fatty Acid Receptor

Free fatty acid receptor 4 (FFA4) has been reported to be a receptor for n-3 fatty acids (FAs). Although n-3 FAs are beneficial for bone health, a role of FFA4 in bone metabolism has been rarely investigated. We noted that FFA4 was more abundantly expressed in both mature osteoclasts and osteoblasts than their respective precursors and that it was activated by docosahexaenoic acid. FFA4 knockout (Ffar4−/−) and wild-type mice exhibited similar bone masses when fed a normal diet. Because fat-1 transgenic (fat-1Tg+) mice endogenously converting n-6 to n-3 FAs contain high n-3 FA levels, we crossed Ffar4−/− and fat-1Tg+ mice over two generations to generate four genotypes of mice littermates: Ffar4+/+;fat-1Tg−, Ffar4+/+;fat-1Tg+, Ffar4−/−;fat-1Tg−, and Ffar4−/−;fat-1Tg+. Female and male littermates were included in ovariectomy- and high-fat diet-induced bone loss models, respectively. Female fat-1Tg+ mice decreased bone loss after ovariectomy both by promoting osteoblastic bone formation and inhibiting osteoclastic bone resorption than their wild-type littermates, only when they had the Ffar4+/+ background, but not the Ffar4−/− background. In a high-fat diet-fed model, male fat-1Tg+ mice had higher bone mass resulting from stimulated bone formation and reduced bone resorption than their wild-type littermates, only when they had the Ffar4+/+ background, but not the Ffar4−/− background. In vitro studies supported the role of FFA4 as n-3 FA receptor in bone metabolism. In conclusion, FFA4 is a dual-acting factor that increases osteoblastic bone formation and decreases osteoclastic bone resorption, suggesting that it may be an ideal target for modulating metabolic bone diseases.

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 Enhancement of Osteoclastic Bone Resorption and Suppression of Osteoblastic Bone Formation in Response to Reduced Mechanical Stress Do Not Occur in the Absence of Osteopontin

2001 ◽  
Vol 193 (3) ◽  
pp. 399-404 ◽  
Author(s):  
Muneaki Ishijima ◽  
Susan R. Rittling ◽  
Teruhito Yamashita ◽  
Kunikazu Tsuji ◽  
Hisashi Kurosawa ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Mechanical Stress ◽  
Bone Matrix ◽  
Osteoclastic Bone Resorption ◽  
Tail Suspension ◽  
Wild Type ◽  
Osteoblastic Bone Formation

Reduced mechanical stress to bone in bedridden patients and astronauts leads to bone loss and increase in fracture risk which is one of the major medical and health issues in modern aging society and space medicine. However, no molecule involved in the mechanisms underlying this phenomenon has been identified to date. Osteopontin (OPN) is one of the major noncollagenous proteins in bone matrix, but its function in mediating physical-force effects on bone in vivo has not been known. To investigate the possible requirement for OPN in the transduction of mechanical signaling in bone metabolism in vivo, we examined the effect of unloading on the bones of OPN−/− mice using a tail suspension model. In contrast to the tail suspension–induced bone loss in wild-type mice, OPN−/− mice did not lose bone. Elevation of urinary deoxypyridinoline levels due to unloading was observed in wild-type but not in OPN−/− mice. Analysis of the mechanisms of OPN deficiency–dependent reduction in bone on the cellular basis resulted in two unexpected findings. First, osteoclasts, which were increased by unloading in wild-type mice, were not increased by tail suspension in OPN−/− mice. Second, measures of osteoblastic bone formation, which were decreased in wild-type mice by unloading, were not altered in OPN−/− mice. These observations indicate that the presence of OPN is a prerequisite for the activation of osteoclastic bone resorption and for the reduction in osteoblastic bone formation in unloaded mice. Thus, OPN is a molecule required for the bone loss induced by mechanical stress that regulates the functions of osteoblasts and osteoclasts.

scholarly journals Lung Transplantation in a Patient With Osteogenesis Imperfecta and Osteoporosis

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A205-A205
Author(s):  
Lena Fan ◽  
Luke J Benvenuto ◽  
Margaret Nolan ◽  
Angela DiMango ◽  
Elizabeth Shane ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Osteogenesis Imperfecta ◽  
Lung Transplantation ◽  
Urinary Calcium ◽  
Multiple Drug ◽  
High Dose ◽  
Full Time ◽  
Restrictive Lung Disease

Abstract Background: Osteogenesis imperfecta (OI) and transplantation (TP) are independently associated with fractures. Yet reports regarding the skeletal effects of organ TP in OI are limited. We report the early skeletal outcomes in an OI patient with osteoporosis who underwent lung TP. Clinical Case: A 35-year-old man with moderate/severe OI and severe bronchiectasis was admitted for progressive respiratory failure and expedited lung TP evaluation. OI was diagnosed at age 10 after sustaining a hairline coccyx fracture when falling off a stool; scoliosis was diagnosed at age 14; additional fractures included ankle (18 y), toes (28 y) and rib (34 y). He had dentogenesis imperfecta, but no hearing loss, easy bruising or OI family history. Bronchiectasis also began at age 10 and progressed, with multiple drug resistant infections and glucocorticoid (GC) treatments. At admission, he was on 6L oxygen and bed-bound from dyspnea. Notably, he had been rejected twice for TP because of his bone disease. Admission medications included calcium, D3, famotidine, inhaled fluticasone, tobramycin, and tiotropium bromide. His exam was notable for height 5’5”, BMI 16.5 kg/m2, kyphoscoliosis, blue sclera and joint laxity. Labs were notable for (mg/dl): serum calcium 9.4, magnesium 2.4, phosphate 4.4; albumin 4.2 g/dl, alkaline phosphatase 75 U/L, 25(OH)D 34 ng/ml, sCTX 535 pg/ml, urinary calcium 370 mg/24 hr. DXA showed T-scores of -4.7 (lumbar spine), -3.3 (femoral neck), -3.2 (total hip), -2.6 (1/3 radius). Endocrinology was consulted about the skeletal risk of lung transplantation. Discussion and Follow-up:The patient’s manifestations of OI increased the risk of adverse skeletal outcomes. His high CTX suggested increased bone resorption, often seen with OI; bone formation was not directly measured but in OI is frequently reduced. Notably, his bronchiectasis was likely related to the OI: in addition to restrictive lung disease in OI, the abnormal type 1 collagen likely alters alveolar structure and elasticity. His risk for post-TP fractures was high given that the expected post-TP bone loss would likely be exacerbated by high dose GCs further increasing bone resorption and reducing presumed low bone formation. Nevertheless, because he had never sustained a major fracture even without OI treatment, the decision was made to proceed. He received zoledronate (ZOL) 5 mg IV and underwent an uncomplicated double lung transplant; initial high dose GCs were tapered to prednisone 10 mg/d. Three months later, he has steadily rising lung function, excellent functional status, and is working full time. A current sCTX of 73 pg/ml suggests that bone loss is not increased. Admittedly, the patient remains within the early high-risk fracture window. Yet this case is the first report to our knowledge which suggests that lung TP in an OI patient treated with ZOL did not lead to fracture in the early post-TP period.

scholarly journals Cortical bone adaptation and mineral mobilization in the subterranean mammalBathyergus suillus(Rodentia: Bathyergidae): effects of age and sex

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e4944 ◽  
Author(s):  
Germán Montoya-Sanhueza ◽  
Anusuya Chinsamy
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Strong Support ◽  
Bone Adaptation ◽  
Medullary Cavity ◽  
Bone Modeling ◽  
Terrestrial Mammals ◽  
Skeletal Homeostasis ◽  
Subterranean Mammal

The patterns of bone modeling and mineral mobilization (skeletal homeostasis) among mammals other than humans and laboratory rodents are still poorly known. In this study we assessed the pattern of bone formation and bone resorption in the femur of a wild population of Cape dune molerats,Bathyergus suillus(n= 41) (Bathyergidae), a solitary subterranean mammal with a marked extended longevity among rodents, and which also lives in a naturally deficient state of vitamin D. In order to determine ontogenetic and sex effects on histomorphometric parameters of transversal undecalcified bone sections, two-way ANOVA, linear mixed-effects model and regression statistical analyses were performed. During ontogeny,B. suillusincreased their cross sectional area, cortical area and cortical thickness, and most importantly, they showed scarce endosteal bone resorption which resulted in a retained medullary cavity size during ontogeny. This resulted in a positively imbalanced bone modeling, where bone formation considerably surpasses bone loss by almost 100-fold in adulthood. This differs markedly from other terrestrial mammals with relatively thin cortical walls. Regarding bone loss and remodeling, three main processes involving intracortical resorption were observed: modeling-related bone loss in early postnatal growth; secondary osteon formation occurring in both sexes; and subendosteal secondary reconstruction observed only in females. The latter is accompanied by females having six-fold more relative bone loss than males, which is evidenced by the development of enlarged resorption cavities (RCs) distributed circumferentially around the medullary cavity. Males have smaller, more circular and randomly distributed RCs. In general, our data indicate no age-related decline in mineral content inB. suillus, and provides strong support for a pattern of sexual dimorphism in skeletal homeostasis, similar to that occurring in humans and other mammals, with females losing more bone throughout aging as compared to males due to reproductive factors. Interestingly as well, despite the high mechanical loads experienced during burrow construction, bone remodeling inB. suillusis kept at very low levels throughout their lifespan, and dense Haversian tissue never forms. This study represents the first comprehensive assessment of skeletal homeostasis in a subterranean mammal, and it enables a better understanding of the complex processes governing the acquisition and maintenance of bone properties in this species with extraordinary fossorial adaptations.

scholarly journals Reduced bone formation in males and increased bone resorption in females drive bone loss in hemophilia A mice

2019 ◽  
Vol 3 (3) ◽  
pp. 288-300 ◽  
Author(s):  
M. Neale Weitzmann ◽  
Susanne Roser-Page ◽  
Tatyana Vikulina ◽  
Daiana Weiss ◽  
Li Hao ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Hemophilia A ◽  
Genetic Disorder ◽  
Clotting Factor ◽  
Female Mice ◽  
Peak Mass ◽  
Traditional Risk Factors ◽  
Traumatic Hemorrhage

Abstract Hemophilia A (HA), a rare X-linked recessive genetic disorder caused by insufficient blood clotting factor VIII, leaves affected individuals susceptible to spontaneous and traumatic hemorrhage. Although males generally exhibit severe symptoms, due to variable X inactivation, females can also be severely impacted. Osteoporosis is a disease of the skeleton predisposing patients to fragility fracture, a cause of significant morbidity and mortality and a common comorbidity in HA. Because the causes of osteoporosis in HA are unclear and in humans confounded by other traditional risk factors for bone loss, in this study, we phenotyped the skeletons of F8 total knockout (F8TKO) mice, an animal model of severe HA. We found that trabecular bone accretion in the axial and appendicular skeletons of male F8TKO mice lagged significantly between 2 and 6 months of age, with more modest cortical bone decline. By contrast, in female mice, diminished bone accretion was mostly limited to the cortical compartment. Interestingly, bone loss was associated with a decline in bone formation in male mice but increased bone resorption in female mice, a possible result of sex steroid insufficiency. In conclusion, our studies reveal a sexual dimorphism in the mechanism driving bone loss in male and female F8TKO mice, preventing attainment of peak bone mass and strength. If validated in humans, therapies aimed at promoting bone formation in males but suppressing bone resorption in females may be indicated to facilitate attainment of peak mass in children with HA to reduce the risk for fracture later in life.

5 alpha-Dihydrotestosterone partially restores cancellous bone volume in osteopenic ovariectomized rats

1994 ◽  
Vol 267 (6) ◽  
pp. E853-E859 ◽  
Author(s):  
J. H. Tobias ◽  
A. Gallagher ◽  
T. J. Chambers
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Cancellous Bone ◽  
Bone Growth ◽  
Bone Volume ◽  
Ovariectomized Rats ◽  
Trabecular Thickness ◽  
Longitudinal Bone Growth ◽  
Periosteal Bone Formation

Although androgens are thought to be important for skeletal maintenance in females and males, little is known about the mechanisms involved. To investigate this question further, we examined the effects of administering 0.01, 0.1, or 1.0 mg/kg 5 alpha-dihydrotestosterone (DHT) for 60 days on the skeleton of ovariectomized rats. Treatment was delayed until 90 days after ovariectomy to enable bone loss to stabilize. We found that ovariectomy markedly reduced cancellous bone volume of the proximal tibial metaphysis due to a combination of loss and thinning of trabeculae. Cancellous bone volume was partially restored by all doses of DHT, with trabecular thickness, but not number, returning to that of sham-operated animals. DHT also stimulated longitudinal bone growth and endosteal and periosteal bone formation and suppressed histomorphometric indexes of cancellous bone resorption. This suggests that DHT influences skeletal metabolism in osteopenic ovariectomized rats both by stimulating bone formation and suppressing resorption, although it is unclear which, if any, of these actions predominate at cancellous sites.

scholarly journals Osteoblasts in osteoporosis: past, emerging, and future anabolic targets

2011 ◽  
Vol 165 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Pierre J Marie ◽  
Moustapha Kassem
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Bone Matrix ◽  
Bone Fragility ◽  
Osteoblastic Cell ◽  
Medline Search ◽  
Cell Functions ◽  
Age Related ◽  
Increased Risk

ObjectiveAge-related bone loss is associated with significant changes in bone remodeling characterized by decreased trabecular and periosteal bone formation relative to bone resorption, resulting in bone fragility and increased risk of fractures. Prevention or reversal of age-related decrease in bone mass and increase in bone fragility has been based on inhibition of bone resorption using anticatabolic drugs. The current challenge is to promote osteoblastogenesis and bone formation to prevent age-related bone deterioration.MethodsA limited number of approved therapeutic molecules are available to activate bone formation. Therefore, there is a need for anabolic drugs that promote bone matrix apposition at the endosteal, endocortical, and periosteal envelopes by increasing the number of osteoblast precursor cells and/or the function of mature osteoblasts. In this study, we review current therapeutics promoting bone formation and anabolic molecules targeting signaling pathways involved in osteoblastogenesis, based on selected full-text articles searched on Medline search from 1990 to 2010.Results and discussionWe present current therapeutic approaches focused on intermittent parathyroid hormone and Wnt signaling agonists/antagonists. We also discuss novel approaches for prevention and treatment of defective bone formation and bone loss associated with aging and osteoporosis. These strategies targeting osteoblastic cell functions may prove to be useful in promoting bone formation and improving bone strength in the aging population.

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