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

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.

Download Full-text

PTH Protects Osteocytes From Oxidative Stress and Cellular Senescence

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.485 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A239-A239

Author(s):

Yuhei Uda ◽

Roberto Santos ◽

Alejandro Kochen ◽

Carly Newell ◽

Tim Y Huang ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Bone Resorption ◽

Bone Loss ◽

Bone Formation ◽

Cellular Senescence ◽

Intracellular Ros ◽

Antioxidant Function ◽

Skeletal Homeostasis ◽

In Cells

Abstract Age-induced osteoporosis is characterized by a progressive decline in bone formation and increase in bone resorption with uncoupled activities of osteoblasts and osteoclasts. Parathyroid hormone (PTH) is used in the clinic to treat osteoporosis due to its anabolic actions on bone via binding to the PTH receptor (PPR). The receptor is highly expressed in cells of the osteoblastic lineage, including osteocytes. Osteocytes are the most abundant cells in bone and serve as a key regulator of bone remodeling. Despite the significant role of PPR signaling in skeletal homeostasis, its function in osteocytes during aging remains unclear. We have gathered preliminary data demonstrating that mice lacking PPR predominantly in osteocytes (Dmp1-PPRKO) have marked age-induced bone loss due to increased bone resorption and suppressed bone formation. These mice, with aging, develop characteristics of skeletal senescence: a decrease in osteoprogenitors and an increase in bone marrow adiposity and p16Ink4a/Cdkn2a expression in bone. Since senescence of cells in the bone microenvironment has been reported as a cause of age-induced bone loss, we hypothesized that PPR signaling protects osteocytes from senescence. To test this hypothesis, we generated osteocytes (Ocy454-12H), in which the PPR expression was ablated using CRISPR/Cas9 technique. Ocy454-12H-PPRKO and Ocy454-12H-PPRCtrl cells were treated with PTH followed by an exposure to hydrogen peroxide (H2O2). High levels of intracellular reactive oxygen species (ROS), including H2O2, promote protein and DNA oxidation, resulting in cell death and senescence. PTH treatment significantly suppressed the increase in H2O2-induced cell death, measured by resazurin-based assays, in PPRCtrl but not in PPRKO cells. We analyzed intracellular ROS levels using a fluorescent probe and found that PTH treatment significantly suppressed the increase in ROS upon H2O2 exposure, suggesting an antioxidant function of PTH in osteocytes. To further investigate if PTH prevents osteocytes from oxidative stress-induced senescence, we examined senescence-associated β-galactosidase (SA β-gal) activity in cells that were treated with PTH followed by an exposure to low doses of H2O2. Compared to untreated and PPRKO groups, treatment with PTH significantly decreased the number of SA β-gal positive cells, demonstrating that PPR signaling protects osteocytes, and possibly other osteoblastic cells, from H2O2-induced cellular senescence. PTH treatment reduced mRNA expression of p21/Cdkn1a. Taken together these results demonstrate that PPR signaling is important to protect osteocytes from cellular senescence.

Download Full-text

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

Journal of Bone and Mineral Research ◽

10.1359/jbmr.2005.20.6.1065 ◽

2005 ◽

Vol 20 (6) ◽

pp. 1065-1074 ◽

Cited By ~ 10

Author(s):

Pierre J. Marie ◽

Monique Hott ◽

Dominique Modrowski ◽

Cinderella de Pollak ◽

Joel Guillemain ◽

...

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Bone Formation

Download Full-text

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

Journal of Bone Biology and Osteoporosis ◽

10.18314/jbo.v1i1.9 ◽

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>

Download Full-text

Osteoporosis in Skin Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms21134749 ◽

2020 ◽

Vol 21 (13) ◽

pp. 4749 ◽

Cited By ~ 4

Author(s):

Maria Maddalena Sirufo ◽

Francesca De Pietro ◽

Enrica Maria Bassino ◽

Lia Ginaldi ◽

Massimo De Martinis

Keyword(s):

Bone Resorption ◽

Bone Formation ◽

Skin Diseases ◽

Public Health Problem ◽

Bone Fragility ◽

Skeletal Disease ◽

Metabolic Bone ◽

Systemic Treatments ◽

Increased Risk ◽

Skeletal Homeostasis

Osteoporosis (OP) is defined as a generalized skeletal disease characterized by low bone mass and an alteration of the microarchitecture that lead to an increase in bone fragility and, therefore, an increased risk of fractures. It must be considered today as a true public health problem and the most widespread metabolic bone disease that affects more than 200 million people worldwide. Under physiological conditions, there is a balance between bone formation and bone resorption necessary for skeletal homeostasis. In pathological situations, this balance is altered in favor of osteoclast (OC)-mediated bone resorption. During chronic inflammation, the balance between bone formation and bone resorption may be considerably affected, contributing to a net prevalence of osteoclastogenesis. Skin diseases are the fourth cause of human disease in the world, affecting approximately one third of the world’s population with a prevalence in elderly men. Inflammation and the various associated cytokine patterns are the basis of both osteoporosis and most skin pathologies. Moreover, dermatological patients also undergo local or systemic treatments with glucocorticoids and immunosuppressants that could increase the risk of osteoporosis. Therefore, particular attention should be paid to bone health in these patients. The purpose of the present review is to take stock of the knowledge in this still quite unexplored field, despite the frequency of such conditions in clinical practice.

Download Full-text

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

Endocrinology ◽

10.1210/en.2015-1855 ◽

2016 ◽

Vol 157 (7) ◽

pp. 2621-2635 ◽

Cited By ~ 23

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.

Download Full-text

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

Journal of Endocrinology ◽

10.1530/joe-18-0153 ◽

2018 ◽

Vol 238 (1) ◽

pp. 13-23 ◽

Cited By ~ 12

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.

Download Full-text

Bone modeling in bromocriptine-treated pregnant and lactating rats: possible osteoregulatory role of prolactin in lactation

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00134.2010 ◽

2010 ◽

Vol 299 (3) ◽

pp. E426-E436 ◽

Cited By ~ 36

Author(s):

Panan Suntornsaratoon ◽

Kannikar Wongdee ◽

Suchandra Goswami ◽

Nateetip Krishnamra ◽

Narattaphol Charoenphandhu

Keyword(s):

Bone Loss ◽

Bone Formation ◽

Trabecular Bone ◽

Formation Rate ◽

Bone Modeling ◽

Mineral Density ◽

Pregnant Rats ◽

Bone Formation Rate ◽

Bone Trabeculae ◽

Bone Gain

The lactogenic hormone prolactin (PRL) directly regulates osteoblast functions in vitro and modulates bone remodeling in nulliparous rats, but its osteoregulatory roles in pregnant and lactating rats with physiological hyperprolactinemia remained unclear. Herein, bone changes were investigated in rats treated with bromocriptine (Bromo), an inhibitor of pituitary PRL release, or Bromo+PRL at different reproductive phases, from mid-pregnancy to late lactation. PRL receptors were strongly expressed in osteoblasts lining bone trabeculae, indicating bone as a target of PRL actions. By using dual energy X-ray absorptiometry, we found a significant increase in bone mineral density in the femora and vertebrae of pregnant rats. Such pregnancy-induced bone gain was, however, PRL independent and may have resulted from the increased cortical thickness. Bone trabeculae were modestly changed during pregnancy as evaluated by bone histomorphometry. On the other hand, lactating rats, especially in late lactation, showed massive bone loss in bone trabeculae but not in cortical shells. Further study in Bromo- and Bromo+PRL-treated rats suggested that PRL contributed to decreases in trabecular bone volume and number and increases in trabecular separation and eroded surface, as well as a paradoxical increase in bone formation rate in late lactation. Uncoupling of trabecular bone formation and resorption was evident in lactating rats, with the latter being predominant. In conclusion, pregnancy mainly induced cortical bone gain, whereas lactation led to trabecular bone loss in both long bones and vertebrae. Although PRL was not responsible for the pregnancy-induced bone gain, it was an important regulator of bone modeling during lactation.

Download Full-text

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

Journal of Experimental Medicine ◽

10.1084/jem.193.3.399 ◽

2001 ◽

Vol 193 (3) ◽

pp. 399-404 ◽

Cited By ~ 167

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.

Download Full-text

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

Theranostics ◽

10.7150/thno.17140 ◽

2016 ◽

Vol 6 (12) ◽

pp. 2183-2195 ◽

Cited By ~ 16

Author(s):

Xiaohong Duan ◽

Jin Liu ◽

Xueni Zheng ◽

Zhe Wang ◽

Yanli Zhang ◽

...

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Bone Formation ◽

Tgf Β1

Download Full-text

Lung Transplantation in a Patient With Osteogenesis Imperfecta and Osteoporosis

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.417 ◽

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.

Download Full-text