scholarly journals Regulation of Bone Mass and Bone Turnover by Neuronal Nitric Oxide Synthase

Endocrinology ◽  
2004 ◽  
Vol 145 (11) ◽  
pp. 5068-5074 ◽  
Author(s):  
Robert J. van’t Hof ◽  
Jeny MacPhee ◽  
Helene Libouban ◽  
Miep H. Helfrich ◽  
Stuart H. Ralston
Keyword(s):  
Nitric Oxide ◽  
Bone Turnover ◽  
Cell Function ◽  
Bone Cells ◽  
Physiological Role ◽  
Bone Cell ◽  
Nodule Formation ◽  
Mineral Density

Abstract Nitric oxide (NO) is produced by NO synthase (NOS) and plays an important role in the regulation of bone cell function. The endothelial NOS isoform is essential for normal osteoblast function, whereas the inducible NOS isoform acts as a mediator of cytokine effects in bone. The role of the neuronal isoform of NOS (nNOS) in bone has been studied little thus far. Therefore, we investigated the role of nNOS in bone metabolism by studying mice with targeted inactivation of the nNOS gene. Bone mineral density (BMD) was significantly higher in nNOS knockout (KO) mice compared with wild-type controls, particularly the trabecular BMD (P < 0.01). The difference in BMD between nNOS KO and control mice was confirmed by histomorphometric analysis, which showed a 67% increase in trabecular bone volume in nNOS KO mice when compared with controls (P < 0.001). This was accompanied by reduced bone remodeling, with a significant reduction in osteoblast numbers and bone formation surfaces and a reduction in osteoclast numbers and bone resorption surfaces. Osteoblasts from nNOS KO mice, however, showed increased levels of alkaline phosphatase and no defects in proliferation or bone nodule formation in vitro, whereas osteoclastogenesis was increased in nNOS KO bone marrow cultures. These studies indicate that nNOS plays a hitherto unrecognized but important physiological role as a stimulator of bone turnover. The low level of nNOS expression in bone and the in vitro behavior of nNOS KO bone cells indicate that these actions are indirect and possibly mediated by a neurogenic relay.

From Mouse to Man: Redefining the Role of Insulin-Like Growth Factor-I in the Acquisition of Bone Mass

2003 ◽  
Vol 228 (3) ◽  
pp. 245-252 ◽  
Author(s):  
Shoshana Yakar ◽  
Clifford J. Rosen
Keyword(s):  
Growth Factor ◽  
Cell Function ◽  
Bone Cells ◽  
Bone Cell ◽  
Insulin Like Growth Factor ◽  
In Vivo Models ◽  
Igf I

The insulin-like growth factor system (IGF) has been linked to the process of bone acquisition through epidemiologic analyses of large cohorts and in vitro studies of bone cells. But the exact relationship between expression of IGF-I in bone and skeletal homeostasis or pathologic conditions, such as osteoporosis, remains poorly defined. Recent advances in genomic engineering have resulted in the development of better in vivo models to test the role of IGF-I during development and maintenance of the adult skeleton. It is now established that skeletal expression of IGF-I is critical for differentiative bone cell function. It may also be essential for the full anabolic effects of parathyroid hormone on trabecular bone and for some component of biomineralization. Evidence from conditional mutagenesis studies suggests that serum IGF-I may represent more than a storage depot or permissive factor during the final phase of skeletal acquisition. This work re-examines the original tenets of the “somatomedin hypothesis” in light of these newer mouse models and their remarkable skeletal phenotypes. The implications are far reaching and suggest that newer approaches for manipulating the IGF regulatory system may one day be useful as therapeutic adjuncts for the treatment of osteoporosis.

Role of calcium in bone maturation arrest after thyroparathyroidectomy in the rat

1977 ◽  
Vol 232 (1) ◽  
pp. F33-F41
Author(s):  
J. M. Burnell ◽  
E. Teubner ◽  
D. Korn ◽  
A. Miller
Keyword(s):  
Cell Function ◽  
Bone Cell ◽  
X Ray Diffraction ◽  
Mineral Density ◽  
Bone Maturation ◽  
Bone Changes ◽  
Chemical Studies ◽  
Normal Increase ◽  
Bone Abnormalities

Thyroparathyroidectomy in the rat results in decreased plasma calcium and magnesium and increased phosphorus. The associated bone changes are decreased calcium, hydroxyproline, carbonate, and wholebone density. Bone magnesium, sodium, mineral density, and percent crystallinity are increased. The delayed matrix formation and mineralization previously identified by histologic techniques are herein characterized by direct measurement as arrest of the normal increase of hydroxyproline/matrix and percent mineral. The bone mineral present is of high density and x-ray-diffraction crystallinity, suggesting a decrease in the mineralization front high in the amorphous phase and/or small nondiffracting crystalloids. The chemical studies reveal that in the absence of available Ca, Mg and Na are substituted, and CO3 is decreased. The restoration of these plasma and bone abnormalities to normal by a diet high in CaCO3 adds further emphasis to the essential role of Ca in bone cell function.

scholarly journals Bone Re/Modeling Is More Dynamic in the Endothelial Nitric Oxide Synthase(−/−) Mouse

Endocrinology ◽  
2006 ◽  
Vol 147 (9) ◽  
pp. 4392-4399 ◽  
Author(s):  
F. Grassi ◽  
X. Fan ◽  
J. Rahnert ◽  
M. N. Weitzmann ◽  
R. Pacifici ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Bone Remodeling ◽  
Bone Cells ◽  
Bone Cell ◽  
High Rate ◽  
Wild Type ◽  
Mineral Density ◽  
Bone Maturation ◽  
Basal Bone ◽  
Endothelial Nitric Oxide

Nitric oxide is a ubiquitous estrogen-regulated signaling molecule that has been implicated in the regulation of bone maturation and remodeling. To better understand the role that bone-cell-secreted nitric oxide plays in ovariectomy-induced modifications of bone turnover, we examined the expression of endothelial NO synthase (eNOS) in bone cells and bone progenitor cells at regular intervals up to 10 wk after acute estrogen deprivation. Ovariectomy led to an anticipated initial decline in bone cell eNOS production, but surprisingly, 17 d after ovariectomy, eNOS expression by bone and marrow stromal cells dramatically rebounded and was maintained at high levels for at least 10 wk after surgery. We examined the long-term consequences of eNOS in the process of ovariectomy-induced bone loss by prospectively analyzing bone mineral density in wild-type and eNOS(−/−) mice for 10 wk after ovariectomy. Ovariectomized eNOS(−/−) mice were observed to undergo an exaggerated state of estrogen-deficiency-induced bone remodeling compared with wild-type controls, suggesting that eNOS may act to mitigate this process. Furthermore, we found that whereas bone formation in estrogen-replete wild-type mice slowed between 14 and 20 wk of age, eNOS knockout mice continued to accrue basal bone mass at a high rate and showed no sign of entering a remodeling stage. Our data suggest that eNOS may play an important role in limiting ovariectomy-induced bone remodeling as well as regulating the transition from basal modeling to remodeling.

scholarly journals The P2Y6 Receptor Stimulates Bone Resorption by Osteoclasts

Endocrinology ◽  
2011 ◽  
Vol 152 (10) ◽  
pp. 3706-3716 ◽  
Author(s):  
Isabel R. Orriss ◽  
Ning Wang ◽  
Geoffrey Burnstock ◽  
Timothy R. Arnett ◽  
Alison Gartland ◽  
...  
Keyword(s):  
Cell Function ◽  
Bone Cell ◽  
Extracellular Nucleotides ◽  
P2y6 Receptor ◽  
Tomographic Analysis ◽  
G Protein Coupled ◽  
Resorptive Activity

Accumulating evidence indicates that extracellular nucleotides, signaling through P2 receptors, play a significant role in bone remodeling. Osteoclasts (the bone-resorbing cell) and osteoblasts (the bone-forming cell) display expression of the G protein-coupled P2Y6 receptor, but the role of this receptor in modulating cell function is unclear. Here, we demonstrate that extracellular UDP, acting via P2Y6 receptors, stimulates the formation of osteoclasts from precursor cells, while also enhancing the resorptive activity of mature osteoclasts. Furthermore, osteoclasts derived from P2Y6 receptor-deficient (P2Y6R−/−) animals displayed defective function in vitro. Using dual energy x-ray absorptiometry scanning and microcomputed tomographic analysis we showed that P2Y6R−/− mice have increased bone mineral content, cortical bone volume, and cortical thickness in the long bones and spine, whereas trabecular bone parameters were unaffected. Histomorphometric analysis showed the perimeter of the bone occupied by osteoclasts on the endocortical and trabecular surfaces was decreased in P2Y6R−/− mice. Taken together these results show the P2Y6 receptor may play an important role in the regulation of bone cell function in vivo.

Response of normal and osteoporotic human bone cells to mechanical stress in vitro

1998 ◽  
Vol 274 (6) ◽  
pp. E1113-E1120 ◽  
Author(s):  
Jozien G. H. Sterck ◽  
Jenneke Klein-Nulend ◽  
Paul Lips ◽  
Elisabeth H. Burger
Keyword(s):  
Nitric Oxide ◽  
Mechanical Stress ◽  
Cell Cultures ◽  
Bone Cells ◽  
Bone Cell ◽  
Human Bone ◽  
Animal Bone ◽  
Bone Cell Cultures

Bone adapts to mechanical stress, and bone cell cultures from animal origin have been shown to be highly sensitive to mechanical stress in vitro. In this study, we tested whether bone cell cultures from human bone biopsies respond to stress in a similar manner as animal bone cells and whether bone cells from osteoporotic patients respond similarly to nonosteoporotic donors. Bone cell cultures were obtained as outgrowth from collagenase-stripped trabecular bone fragments from 17 nonosteoporotic donors between 7 and 77 yr of age and from 6 osteoporotic donors between 42 and 72 yr of age. After passage, the cells were mechanically stressed by treatment with pulsating fluid flow (PFF; 0.7 ± 0.03 Pa at 5 Hz for 1 h) to mimic the stress-driven flow of interstitial fluid through the bone canaliculi, which is likely the stimulus for mechanosensation in bone in vivo. Similar to earlier studies in rodent and chicken bone cells, the bone cells from nonosteoporotic donors responded to PFF with enhanced release of prostaglandin E2(PGE2) and nitric oxide as well as a reduced release of transforming growth factor-β (TGF-β). The upregulation of PGE2 but not the other responses continued for 24 h after 1 h of PFF treatment. The bone cells from osteoporotic donors responded in a similar manner as the nonosteoporotic donors except for the long-term PGE2 release. The PFF-mediated upregulation of PGE2 release during 24 h of postincubation after 1 h of PFF was significantly reduced in osteoporotic patients compared with six age-matched controls as well as with the whole nonosteoporotic group. These results indicate that enhanced release of PGE2 and nitric oxide, as well as reduced release of TGF-β, is a characteristic response of human bone cells to fluid shear stress, similar to animal bone cells. The results also suggest that bone cells from osteoporotic patients may be impaired in their long-term response to mechanical stress.

scholarly journals The Role of Connexin Channels in the Response of Mechanical Loading and Unloading of Bone

2020 ◽  
Vol 21 (3) ◽  
pp. 1146 ◽  
Author(s):  
Manuel A. Riquelme ◽  
Eduardo R. Cardenas ◽  
Huiyun Xu ◽  
Jean X. Jiang
Keyword(s):  
Mechanical Loading ◽  
Cell Function ◽  
Bone Cells ◽  
Bone Cell ◽  
Research Progress ◽  
Related Factor ◽  
Channel Network ◽  
Gap Junction Channel ◽  
Major Player

The skeleton adapts to mechanical loading to promote bone formation and remodeling. While most bone cells are involved in mechanosensing, it is well accepted that osteocytes are the principal mechanosensory cells. The osteocyte cell body and processes are surrounded by a fluid-filled space, forming an extensive lacuno-canalicular network. The flow of interstitial fluid is a major stress-related factor that transmits mechanical stimulation to bone cells. The long dendritic processes of osteocytes form a gap junction channel network connecting not only neighboring osteocytes, but also cells on the bone surface, such as osteoblasts and osteoclasts. Mechanosensitive osteocytes also form hemichannels that mediate the communication between the cytoplasmic and extracellular microenvironment. This paper will discuss recent research progress regarding connexin (Cx)-forming gap junctions and hemichannels in osteocytes, osteoblasts, and other bone cells, including those richly expressing Cx43. We will then cover the recent progress regarding the regulation of these channels by mechanical loading and the role of integrins and signals in mediating Cx43 channels, and bone cell function and viability. Finally, we will summarize the recent studies regarding bone responses to mechanical unloading in Cx43 transgenic mouse models. The osteocyte has been perceived as the center of bone remodeling, and connexin channels enriched in osteocytes are a likely major player in meditating the function of bone. Based on numerous studies, connexin channels may present as a potential new therapeutic target in the treatment of bone loss and osteoporosis. This review will primarily focus on Cx43, with some discussion in other connexins expressed in bone cells.

scholarly journals Review on material parameters to enhance bone cell function in vitro and in vivo

2020 ◽  
Vol 48 (5) ◽  
pp. 2039-2050
Author(s):  
Eric Madsen ◽  
Merjem Mededovic ◽  
David H. Kohn
Keyword(s):  
Cell Function ◽  
Bone Cells ◽  
Bone Cell ◽  
Bone Augmentation ◽  
Material Parameters ◽  
Specific Material ◽  
Resorbable Implants ◽  
Resorbable Materials

Bone plays critical roles in support, protection, movement, and metabolism. Although bone has an innate capacity for regeneration, this capacity is limited, and many bone injuries and diseases require intervention. Biomaterials are a critical component of many treatments to restore bone function and include non-resorbable implants to augment bone and resorbable materials to guide regeneration. Biomaterials can vary considerably in their biocompatibility and bioactivity, which are functions of specific material parameters. The success of biomaterials in bone augmentation and regeneration is based on their effects on the function of bone cells. Such functions include adhesion, migration, inflammation, proliferation, communication, differentiation, resorption, and vascularization. This review will focus on how different material parameters can enhance bone cell function both in vitro and in vivo.

scholarly journals Activation of the P2Y2 receptor regulates bone cell function by enhancing ATP release

2017 ◽  
Vol 233 (3) ◽  
pp. 341-356 ◽  
Author(s):  
Isabel R Orriss ◽  
Dilek Guneri ◽  
Mark O R Hajjawi ◽  
Kristy Shaw ◽  
Jessal J Patel ◽  
...  
Keyword(s):  
Cell Function ◽  
Bone Cells ◽  
Atp Release ◽  
Fold Increase ◽  
Bone Cell ◽  
Age Related ◽  
Key Factor ◽  
Osteoclast Function ◽  
Bone Mineralisation

Bone cells constitutively release ATP into the extracellular environment where it acts locally via P2 receptors to regulate bone cell function. Whilst P2Y2 receptor stimulation regulates bone mineralisation, the functional effects of this receptor in osteoclasts remain unknown. This investigation used the P2Y2 receptor knockout (P2Y2R−/−) mouse model to investigate the role of this receptor in bone. MicroCT analysis of P2Y2R−/− mice demonstrated age-related increases in trabecular bone volume (≤48%), number (≤30%) and thickness (≤17%). In vitro P2Y2R−/− osteoblasts displayed a 3-fold increase in bone formation and alkaline phosphatase activity, whilst P2Y2R−/− osteoclasts exhibited a 65% reduction in resorptive activity. Serum cross-linked C-telopeptide levels (CTX, resorption marker) were also decreased (≤35%). The resorption defect in P2Y2R−/− osteoclasts was rescued by the addition of exogenous ATP, suggesting that an ATP deficit could be a key factor in the reduced function of these cells. In agreement, we found that basal ATP release was reduced up to 53% in P2Y2R−/− osteoclasts. The P2Y2 receptor agonists, UTP and 2-thioUTP, increased osteoclast activity and ATP release in wild-type but not in P2Y2R−/− cells. This indicates that the P2Y2 receptor may regulate osteoclast function indirectly by promoting ATP release. UTP and 2-thioUTP also stimulate ATP release from osteoblasts suggesting that the P2Y2 receptor exerts a similar function in these cells. Taken together, our findings are consistent with the notion that the primary action of P2Y2 receptor signalling in bone is to regulate extracellular ATP levels.

Megakaryocyte-driven changes in bone health: lessons from mouse models of myelofibrosis and related disorders

2021 ◽  
Author(s):  
Mariya Stavnichuk ◽  
Svetlana V. Komarova
Keyword(s):  
Bone Marrow ◽  
Mouse Models ◽  
Cell Function ◽  
Bone Cells ◽  
Bone Marrow Cells ◽  
Bone Cell ◽  
Bone Architecture ◽  
Bone Homeostasis

Over the years, numerous studies demonstrated reciprocal communications between processes of bone marrow hematopoiesis and bone remodeling. Megakaryocytes, rare bone marrow cells responsible for platelet production, were demonstrated to be involved in bone homeostasis. Myelofibrosis, characterized by an increase in pleomorphic megakaryocytes in the bone marrow, commonly leads to the development of osteosclerosis. In vivo, an increase in megakaryocyte number was shown to result in osteosclerosis in GATA-1low, NF-E2-/-, TPOhigh, Mpllf/f;PF4cre, Lnk-/-, Mpig6b-/-, Mpig6bfl/fl;Gp1ba-Cr+/KI, Pt-vWD mouse models. In vitro, megakaryocytes stimulate osteoblast proliferation and have variable effects on osteoclast proliferation and activity through soluble factors and direct cell-cell communications. Intriguingly, new studies revealed that the ability of megakaryocytes to communicate with bone cells is affected by the age and sex of animals. This mini-review summarises changes seen in bone architecture and bone cell function in mouse models with an elevated number of megakaryocytes and the effects megakaryocytes have on osteoblasts and osteoclasts in vitro, and discusses potential molecular players that can mediate these effects.

scholarly journals The Activity of Peptides of the Calcitonin Family in Bone

2019 ◽  
Vol 99 (1) ◽  
pp. 781-805 ◽  
Author(s):  
Dorit Naot ◽  
David S. Musson ◽  
Jillian Cornish
Keyword(s):  
Bone Resorption ◽  
Bone Turnover ◽  
Biological Activities ◽  
Physiological Role ◽  
Positive Effects ◽  
Osteoblast Activity ◽  
Calcitonin Gene ◽  
The Relationship

Calcitonin was discovered over 50 yr ago as a new hormone that rapidly lowers circulating calcium levels. This effect is caused by the inhibition of calcium efflux from bone, as calcitonin is a potent inhibitor of bone resorption. Calcitonin has been in clinical use for conditions of accelerated bone turnover, including Paget’s disease and osteoporosis; although in recent years, with the development of drugs that are more potent inhibitors of bone resorption, its use has declined. A number of peptides that are structurally similar to calcitonin form the calcitonin family, which currently includes calcitonin gene–related peptides (αCGRP and βCGRP), amylin, adrenomedullin, and intermedin. Apart from being structurally similar, the peptides signal through related receptors and have some overlapping biological activities, although other activities are peptide specific. In bone, in vitro studies and administration of the peptides to animals generally found inhibitory effects on osteoclasts and bone resorption and positive effects on osteoblasts and bone formation. Surprisingly, studies in genetically modified mice have demonstrated that the physiological role of calcitonin appears to be the inhibition of osteoblast activity and bone turnover, whereas amylin inhibits osteoclast activity. The review article focuses on the activities of peptides of the calcitonin family in bone and the challenges in understanding the relationship between the pharmacological effects and the physiological roles of these peptides.

Sign in / Sign up

Export Citation Format

Share Document