scholarly journals MECHANISMS IN ENDOCRINOLOGY: Genetics of human bone formation

2017 ◽  
Vol 177 (2) ◽  
pp. R69-R83 ◽  
Author(s):  
Eveline Boudin ◽  
Wim Van Hul
Keyword(s):  
Bone Formation ◽  
Bone Mass ◽  
Bone Homeostasis ◽  
Low Bone Mass ◽  
Treatment Of Osteoporosis ◽  
Regulatory Pathways ◽  
Complex Disorders ◽  
Monogenic Disorders ◽  
Genes Encoding ◽  
Bone Remodelling Process

Throughout life, bone is continuously remodelled to be able to fulfil its multiple functions. The importance of strictly regulating the bone remodelling process, which is defined by the sequential actions of osteoclasts and osteoblasts, is shown by a variety of disorders with abnormalities in bone mass and strength. The best known and most common example of such a disorder is osteoporosis, which is marked by a decreased bone mass and strength that consequently results in an increased fracture risk. As osteoporosis is a serious health problem, a large number of studies focus on elucidating the aetiology of the disease as well as on the identification of novel therapeutic targets for the treatment of osteoporotic patients. These studies have demonstrated that a large amount of variation in bone mass and strength is often influenced by genetic variation in genes encoding important regulators of bone homeostasis. Throughout the years, studies into the genetic causes of osteoporosis as well as several rare monogenic disorders with abnormal high or low bone mass and strength have largely increased the knowledge on regulatory pathways important for bone resorption and formation. This review gives an overview of genes and pathways that are important for the regulation of bone formation and that are identified through their involvement in monogenic and complex disorders with abnormal bone mass. Furthermore, novel bone-forming strategies for the treatment of osteoporosis that resulted from these discoveries, such as antibodies against sclerostin, are discussed as well.

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 Bone Formation Markers in Adults with Mild Osteogenesis Imperfecta

2007 ◽  
Vol 53 (6) ◽  
pp. 1109-1114 ◽  
Author(s):  
Tim Cundy ◽  
Anne Horne ◽  
Mark Bolland ◽  
Greg Gamble ◽  
James Davidson
Keyword(s):  
Alkaline Phosphatase ◽  
Bone Formation ◽  
Bone Mass ◽  
Osteogenesis Imperfecta ◽  
Plasma Concentrations ◽  
Bone Alkaline Phosphatase ◽  
Type I ◽  
Low Bone Mass ◽  
Bone Formation Markers ◽  
Discriminant Ability

Abstract Background: Plasma concentrations of procollagen peptides are decreased in osteogenesis imperfecta (OI), whereas other bone formation markers may be increased. We examined the utility of combining these markers in the diagnosis of OI in adults. Methods: We measured plasma concentrations of procollagen-1 N-peptide (P1NP), osteocalcin, and bone alkaline phosphatase in 24 patients with nondeforming OI, 25 patients with low bone mass due to other causes, and 38 age- and sex-matched controls. The discriminant ability of various test combinations was assessed by the construction of ROC curves. Results: The median (range) ratio of osteocalcin to P1NP was significantly greater in patients with type I OI [1.75 (0.80–3.86)] than in controls [0.59 (0.34–0.90)] and patients with other causes of low bone mass [0.48 (0.05–1.38); P &lt;0.0001]. This ratio allowed nearly complete differentiation between healthy controls and patients with type I OI, but not patients with type IV OI. With a cutoff of 0.97 for osteocalcin:P1NP, the sensitivity and specificity were maximized at 95% (95% CI 76%–100%) and 88% (69%–97%), respectively, for patients with other causes of low bone mass vs those with type I OI only. For patients with other causes of low bone mass vs all OI patients, sensitivity and specificity were 83% (63%–95%) and 88% (69%–97%), respectively. The addition of bone alkaline phosphatase data did not improve the discriminant ability of the osteocalcin:P1NP ratio. Conclusions: The osteocalcin:P1NP ratio is a sensitive and specific test for type I OI in adults, but it has less utility in the diagnosis of other types of nondeforming OI.

scholarly journals Effects of Estrogen Receptor and Wnt Signaling Activation on Mechanically Induced Bone Formation in a Mouse Model of Postmenopausal Bone Loss

2020 ◽  
Vol 21 (21) ◽  
pp. 8301
Author(s):  
Astrid Liedert ◽  
Claudia Nemitz ◽  
Melanie Haffner-Luntzer ◽  
Fabian Schick ◽  
Franz Jakob ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Bone Loss ◽  
Bone Formation ◽  
Bone Mass ◽  
Postmenopausal Bone Loss ◽  
Paracrine Factors ◽  
Treatment Of Osteoporosis ◽  
Ovariectomized Mice ◽  
Underlying Mechanisms ◽  
Signaling Activation

In the adult skeleton, bone remodeling is required to replace damaged bone and functionally adapt bone mass and structure according to the mechanical requirements. It is regulated by multiple endocrine and paracrine factors, including hormones and growth factors, which interact in a coordinated manner. Because the response of bone to mechanical signals is dependent on functional estrogen receptor (ER) and Wnt/β-catenin signaling and is impaired in postmenopausal osteoporosis by estrogen deficiency, it is of paramount importance to elucidate the underlying mechanisms as a basis for the development of new strategies in the treatment of osteoporosis. The present study aimed to investigate the effectiveness of the activation of the ligand-dependent ER and the Wnt/β-catenin signal transduction pathways on mechanically induced bone formation using ovariectomized mice as a model of postmenopausal bone loss. We demonstrated that both pathways interact in the regulation of bone mass adaption in response to mechanical loading and that the activation of Wnt/β-catenin signaling considerably increased mechanically induced bone formation, whereas the effects of estrogen treatment strictly depended on the estrogen status in the mice.

Teriparatide: Its Use in the Treatment of Osteoporosis

2011 ◽  
Vol 3 ◽  
pp. CMT.S2358 ◽  
Author(s):  
Charles A. Inderjeeth ◽  
Kien Chan ◽  
Paul Glendenning
Keyword(s):  
Bone Formation ◽  
Bone Mass ◽  
Animal Studies ◽  
Safety Data ◽  
Ageing Population ◽  
Mineral Density ◽  
Duration Of Treatment ◽  
Treatment Of Osteoporosis ◽  
Teriparatide Treatment ◽  
Increased Risk

The prevalence of osteoporosis is likely to rise with the increase in life expectancy of an ageing population. Current first line therapies for the treatment of osteoporosis are predominantly anti-resorptive. Teriparatide is a first in class, anabolic agent with a unique mechanism that results in increased bone formation. Daily subcutaneous injection for 6–24 months was effective in reducing vertebral and non-vertebral fracture rates, in improving bone mineral density (BMD) and in increasing bone formation rates in postmenopausal osteoporosis, with effects persisting following treatment cessation. Similar benefits on bone mass and bone formation were seen in men with osteoporosis and glucocorticoid induced osteoporosis. Beneficial effects on bone mass have been demonstrated in treatment naive subjects treated with teriparatide alone, sequentially with anti-resorptive therapy and concomitantly with some, but not all, anti-resorptive treatments due to an early blunting of the anabolic effect. Teriparatide is generally well tolerated. However, the high treatment cost and inconvenient mode of administration has limited it's use to patients with osteoporosis who have experienced an unsatisfactory response, who are intolerant to other osteoporosis therapies, or to patients at very high risk of fracture. Teriparatide treatment is currently restricted to a total lifetime treatment dose of 18 months of daily subcutaneous therapy due to concerns from animal studies suggesting an increased risk of osteosarcoma. More safety data may permit a longer duration of treatment in the future but will necessitate prolonged human studies. Teriparatide may serve a more prominent role in the treatment of older patients who continue to fracture despite low bone turnover or sustain side effects with anti-resorptive therapy.

scholarly journals Epo/EpoR signaling in osteoprogenitor cells is essential for bone homeostasis and Epo-induced bone loss

Bone Research ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Martina Rauner ◽  
Marta Murray ◽  
Sylvia Thiele ◽  
Deepika Watts ◽  
Drorit Neumann ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Bone Mass ◽  
Marker Genes ◽  
Bone Homeostasis ◽  
Bone Formation Rate ◽  
Osteoprogenitor Cells ◽  
Cell Parameters ◽  
Female Mice ◽  
Osteoblast Activity

AbstractHigh erythropoietin (Epo) levels are detrimental to bone health in adult organisms. Adult mice receiving high doses of Epo lose bone mass due to suppressed bone formation and increased bone resorption. In humans, high serum Epo levels are linked to fractures in elderly men. Our earlier studies indicated that Epo modulates osteoblast activity; however, direct evidence that Epo acts via its receptor (EpoR) on osteoblasts in vivo is still missing. Here, we created mice lacking EpoR in osteoprogenitor cells to specifically address this gap. Deletion of EpoR in osteoprogenitors (EpoR:Osx-cre, cKO) starting at 5 weeks of age did not alter red blood cell parameters but increased vertebral bone volume by 25% in 12-week-old female mice. This was associated with low bone turnover. Histological (osteoblast number, bone formation rate) and serum (P1NP, osteocalcin) bone formation parameters were all reduced, as were the number of osteoclasts and TRAP serum level. Differentiation of osteoblast precursors isolated from cKO versus control mice resulted in lower expression of osteoblast marker genes including Runx2, Alp, and Col1a1 on day 21, whereas the mineralization capacity was similar. Moreover, the RANKL/OPG ratio, which determines the osteoclast-supporting potential of osteoblasts, was substantially decreased by 50%. Similarly, coculturing cKO osteoblasts with control or cKO osteoclast precursors produced significantly fewer osteoclasts than coculture with control osteoblasts. Finally, exposing female mice to Epo pumps (10 U·d−1) for 4 weeks resulted in trabecular bone loss (−25%) and increased osteoclast numbers (1.7-fold) in control mice only, not in cKO mice. Our data show that EpoR in osteoprogenitors is essential in regulating osteoblast function and osteoblast-mediated osteoclastogenesis via the RANKL/OPG axis. Thus, osteogenic Epo/EpoR signaling controls bone mass maintenance and contributes to Epo-induced bone loss.

JunD suppresses bone formation and contributes to low bone mass induced by estrogen depletion

2008 ◽  
Vol 103 (4) ◽  
pp. 1037-1045 ◽  
Author(s):  
Aya Kawamata ◽  
Yayoi Izu ◽  
Haruna Yokoyama ◽  
Teruo Amagasa ◽  
Erwin F. Wagner ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Mass ◽  
Low Bone Mass ◽  
Estrogen Depletion

scholarly journals Bone modeling and remodeling: potential as therapeutic targets for the treatment of osteoporosis

2016 ◽  
Vol 8 (6) ◽  
pp. 225-235 ◽  
Author(s):  
Bente Langdahl ◽  
Serge Ferrari ◽  
David W. Dempster
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Bone Mass ◽  
Bone Remodeling ◽  
De Novo ◽  
Skeletal Development ◽  
Cathepsin K ◽  
Bone Modeling ◽  
Treatment Of Osteoporosis ◽  
Age Related

The adult skeleton is renewed by remodeling throughout life. Bone remodeling is a process where osteoclasts and osteoblasts work sequentially in the same bone remodeling unit. After the attainment of peak bone mass, bone remodeling is balanced and bone mass is stable for one or two decades until age-related bone loss begins. Age-related bone loss is caused by increases in resorptive activity and reduced bone formation. The relative importance of cortical remodeling increases with age as cancellous bone is lost and remodeling activity in both compartments increases. Bone modeling describes the process whereby bones are shaped or reshaped by the independent action of osteoblast and osteoclasts. The activities of osteoblasts and osteoclasts are not necessarily coupled anatomically or temporally. Bone modeling defines skeletal development and growth but continues throughout life. Modeling-based bone formation contributes to the periosteal expansion, just as remodeling-based resorption is responsible for the medullary expansion seen at the long bones with aging. Existing and upcoming treatments affect remodeling as well as modeling. Teriparatide stimulates bone formation, 70% of which is remodeling based and 20–30% is modeling based. The vast majority of modeling represents overflow from remodeling units rather than de novo modeling. Denosumab inhibits bone remodeling but is permissive for modeling at cortex. Odanacatib inhibits bone resorption by inhibiting cathepsin K activity, whereas modeling-based bone formation is stimulated at periosteal surfaces. Inhibition of sclerostin stimulates bone formation and histomorphometric analysis demonstrated that bone formation is predominantly modeling based. The bone-mass response to some osteoporosis treatments in humans certainly suggests that nonremodeling mechanisms contribute to this response and bone modeling may be such a mechanism. To date, this has only been demonstrated for teriparatide, however, it is clear that rediscovering a phenomenon that was first observed more half a century ago will have an important impact on our understanding of how new antifracture treatments work.

scholarly journals A Study to Assess the Effectiveness of Self Instructional Module on Knowledge Regarding Prevention of Osteoporosis Among the Middle Aged Women in Selected Hospital, Bangalore

2021 ◽  
pp. 184-187
Author(s):  
Mr. Sujin Thomas
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Mass ◽  
Bone Tissue ◽  
Peak Bone Mass ◽  
Bone Matrix ◽  
Bone Mass Density ◽  
Low Bone Mass ◽  
Structural Deterioration ◽  
Increased Risk

Bone is living, growing tissue. It is made mostly of collagen, a protein that provides a soft framework, and calcium phosphate, a mineral that adds strength and hardens the framework. This combination of collagen and calcium makes bone both flexible and strong, which in turn helps bone to withstand stress.1 More than 99 percent of the body’s calcium is contained in the bones and teeth. The remaining 1 percent is found in the blood. Throughout one’s lifetime, old bone is removed (resorption) and new bone is added to the skeleton (formation). During childhood and teenage years, new bone is added faster than old bone is removed. As a result, bones become larger, heavier, and denser. Bone formation outpaces resorption until peak bone mass (maximum bone density and strength) is reached around age 30. After that time, bone resorption slowly begins to exceed bone formation. For women, bone loss is fastest in the first few years after menopause, and it continues into the postmenopausal years. Osteoporosis, or porous bone, is a disease characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility and an increased risk of fractures of the hip, spine, and wrist. Osteoporosis is more likely to develop if you did not reach optimal peak bone mass during your bone-building years. Women are at a greater risk than men, especially women who are thin or have a small frame, as are those of advanced age. Women who are postmenopausal, including those who have had early or surgically induced menopause, or abnormal or absence of menstrual periods, are at greater risk. Cigarette smoking, eating disorders such as anorexia nervosa or bulimia, low amounts of calcium in the diet, heavy alcohol consumption, inactive lifestyle, and use of certain medications, such as corticosteroids and anticonvulsants, are also risk factors for osteoporopsis.2 The underlying mechanism in all cases of osteoporosis is an imbalance between bone resorption and bone formation. In normal bone, matrix remodeling of bone is constant; up to 10% of all bone mass may be undergoing remodeling at any point in time. The process takes place in bone multicellular units (BMUs) as first described by Frost & Thomas in 1963. Osteoclasts are assisted by transcription factor PU.1 to degrade the bone matrix, while osteoblasts rebuild the bone matrix. Low bone mass density can then occur when osteoclasts are degrading the bone matrix faster than the osteoblasts are rebuilding the bone. The three main mechanisms by which osteoporosis develops are an inadequate peak bone mass (the skeleton develops insufficient mass and strength during growth), excessive bone resorption, and inadequate formation of new bone during remodeling. An interplay of these three mechanisms underlies the development of fragile bone tissue. Hormonal factors strongly determine the rate of bone resorption; lack of estrogen (e.g. as a result of menopause) increases bone resorption, as well as decreasing the deposition of new bone that normally takes place in weight-bearing bones.this leads to weakening and softening of bones the bones become soft and it will prone to get fracture or collapse.

scholarly journals The Effect of Leptin on Bone - an Evolving Concept of Action

2008 ◽  
pp. S143-S151
Author(s):  
V Cirmanová ◽  
M Bayer ◽  
L Stárka ◽  
K Zajíčková
Keyword(s):  
Bone Mass ◽  
Cell Lineage ◽  
Osteoblastic Cell ◽  
Treatment Of Osteoporosis ◽  
Regulatory Pathways ◽  
Osteoblast Activity ◽  
Anabolic Treatment ◽  
Trabecular Bone Mass ◽  
Regulate Food Intake ◽  
Energy Deprivation

Leptin, a cytokine-like hormone secreted by adipocytes, is known to regulate food intake but has also emerged as a significant factor in the regulation of bone mass. In humans, states of energy deprivation with low serum leptin have been associated with low bone mass. In mice, leptin deficiency led to increased trabecular bone mass with overall decrease in cortical bone. Leptin regulates bone metabolism indirectly in the hypothalamus thereby activating the sympathetic nervous system (SNS). In addition to the SNS, leptin also interacts with various hypothalamic neuropeptides, such as cocaine- and amphetamine-regulated transcript, neuropeptide Y and/or neuromedin U, which might modulate the effects of leptin on bone. In osteoblasts sympathetic signaling is further gated by the transcriptional factors called molecular clock. As a result, bone loss is accelerated showing that the central effect of leptin seems to be antiosteogenic. Additionally, leptin has a direct anabolic effect within the bone driving the differentiation of bone marrow stem cells into the osteoblastic cell lineage. Besides the interaction between the central and peripheral pathways, the overall effect of leptin on bone might be bimodal depending on leptin serum concentrations. Regulatory pathways triggering osteoblast activity might open new possibilities for anabolic treatment of osteoporosis.

scholarly journals IL-23 receptor deficiency results in lower bone mass via indirect regulation of bone formation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Wida Razawy ◽  
Celso H. Alves ◽  
Marijke Koedam ◽  
Patrick S. Asmawidjaja ◽  
Adriana M. C. Mus ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Mass ◽  
Cortical Bone ◽  
Bone Growth ◽  
Osteoclast Differentiation ◽  
Bone Homeostasis ◽  
Littermate Control ◽  
Cortical Bone Mass

AbstractThe IL-23 receptor (IL-23R) signaling pathway has pleiotropic effects on the differentiation of osteoclasts and osteoblasts, since it can inhibit or stimulate these processes via different pathways. However, the potential role of this pathway in the regulation of bone homeostasis remains elusive. Therefore, we studied the role of IL-23R signaling in physiological bone remodeling using IL-23R deficient mice. Using µCT, we demonstrate that 7-week-old IL-23R−/− mice have similar bone mass as age matched littermate control mice. In contrast, 12-week-old IL-23R−/− mice have significantly lower trabecular and cortical bone mass, shorter femurs and more fragile bones. At the age of 26 weeks, there were no differences in trabecular bone mass and femur length, but most of cortical bone mass parameters remain significantly lower in IL-23R−/− mice. In vitro osteoclast differentiation and resorption capacity of 7- and 12-week-old IL-23R−/− mice are similar to WT. However, serum levels of the bone formation marker, PINP, are significantly lower in 12-week-old IL-23R−/− mice, but similar to WT at 7 and 26 weeks. Interestingly, Il23r gene expression was not detected in in vitro cultured osteoblasts, suggesting an indirect effect of IL-23R. In conclusion, IL-23R deficiency results in temporal and long-term changes in bone growth via regulation of bone formation.

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