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 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 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.

scholarly journals Responses of primary osteoblasts and osteoclasts from hemizygous β-globin knockout thalassemic mice with elevated plasma glucose to 1,25-dihydroxyvitamin D3

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Narattaphol Charoenphandhu ◽  
Ratchaneevan Aeimlapa ◽  
Supagarn Sooksawanwit ◽  
Jirawan Thongbunchoo ◽  
Jarinthorn Teerapornpuntakit ◽  
...  
Keyword(s):  
Bone Loss ◽  
Prolonged Exposure ◽  
Cell Function ◽  
Calcium Absorption ◽  
Bone Cells ◽  
Cathepsin K ◽  
Bone Cell ◽  
Aberrant Expression ◽  
High Blood Glucose ◽  
Extracellular Glucose

Abstract β-thalassemia is often associated with hyperglycemia, osteoporosis and increased fracture risk. However, the underlying mechanisms of the thalassemia-associated bone loss remain unclear. It might result from abnormal activities of osteoblasts and osteoclasts, and perhaps prolonged exposure to high extracellular glucose. Herein, we determined the rate of duodenal calcium transport in hemizygous β-globin knockout thalassemic (BKO) mice. Their bones were collected for primary osteoblast and osteoclast culture. We found that BKO mice had lower calcium absorption than their wild-type (WT) littermates. Osteoblasts from BKO mice showed aberrant expression of osteoblast-specific genes, e.g., Runx2, alkaline phosphatase and osteocalcin, which could be partially restored by 1,25(OH)2D3 treatment. However, the mRNA expression levels of RANK, calcitonin receptor (Calcr), c-Fos, NFATc1, cathepsin K and DMT1 were similar in both BKO and WT groups. Exposure to high extracellular glucose modestly but significantly affected the expression of osteoclast-specific markers in WT osteoclasts with no significant effect on osteoblast-specific genes in WT osteoblasts. Thus, high glucose alone was unable to convert WT bone cells to BKO-like bone cells. In conclusion, the impaired calcium absorption and mutation-related aberrant bone cell function rather than exposure to high blood glucose were likely to be the principal causes of thalassemic bone loss.

scholarly journals The effects of synthetic 19-norprogestins on osteoblastic cell function are mediated by their non-phenolic reduced metabolites

2007 ◽  
Vol 193 (3) ◽  
pp. 493-504 ◽  
Author(s):  
Juana Enríquez ◽  
Ana Elena Lemus ◽  
Jesús Chimal-Monroy ◽  
Higinio Arzate ◽  
Gustavo A García ◽  
...  
Keyword(s):  
Cell Function ◽  
Bone Cells ◽  
Neonatal Rat ◽  
Osteoblastic Cell ◽  
Osteoblast Proliferation ◽  
Mineral Deposition ◽  
Proliferation And Differentiation ◽  
Derivatives Of ◽  
Rat Osteoblasts

The key role of estrogens on osteoblastic cell function is well documented; however, the role of progesterone (P) and synthetic progestins remains controversial. While several reports indicate that P has no significant effects on bone cells, a number of clinical studies have shown that 19-norprogestins restore postmenopausal bone loss. The mechanisms by which 19-norprogestins induce estrogen-like effects on bone cells are not fully understood. To assess whether the actions of 19-norprogestins on osteoblasts are mediated by their non-phenolic metabolites, we studied the effects of norethisterone (NET), levonorgestrel (LNG), and two of their A-ring reduced derivatives upon cell proliferation and differentiation in neonatal rat osteoblasts. Osteoblast function was assessed by determining cell DNA, cell-associated osteocalcin and calcium content, alkaline phosphatase activity, and mineral deposition. P failed to induce changes on osteoblasts, while NET and LNG exerted a number of actions. The most striking finding was that the 3β,5α- and 3α,5α-tetrahydro derivatives of NET and LNG induced osteoblast proliferation and differentiation with higher potency than those exerted by their parent compounds, mimicking the effects of estradiol. Interestingly, osteoblast differentiation and mineral deposition induced by NET and LNG were abolished by finasteride, a 5α-reductases inhibitor, while the potent effect on osteoblast proliferation induced by progestin derivatives was abolished by a steroidal antiestrogen. Results demonstrate that A-ring reduced derivatives of NET and LNG exhibit intrinsic estrogen-like potency on rat osteoblasts, offering a plausible explanation for the mechanism of action of 19-norprogestins in bone restoration in postmenopausal women and providing new insights for hormone replacement therapy research.

scholarly journals 40 YEARS OF IGF1: Role of IGF1 and EFN–EPH signaling in skeletal metabolism

2018 ◽  
Vol 61 (1) ◽  
pp. T87-T102 ◽  
Author(s):  
Richard C Lindsey ◽  
Charles H Rundle ◽  
Subburaman Mohan
Keyword(s):  
Signaling Pathways ◽  
Bone Growth ◽  
Cell Function ◽  
Skeletal Development ◽  
Cell Types ◽  
Bone Cell ◽  
Fracture Repair ◽  
Development And Differentiation ◽  
Major Mediator

Insulin-like growth factor 1(IGF1) and ephrin ligand (EFN)–receptor (EPH) signaling are both crucial for bone cell function and skeletal development and maintenance. IGF1 signaling is the major mediator of growth hormone-induced bone growth, but a host of different signals and factors regulate IGF1 signaling at the systemic and local levels. Disruption of the Igf1 gene results in reduced peak bone mass in both experimental animal models and humans. Additionally, EFN–EPH signaling is a complex system which, particularly through cell–cell interactions, contributes to the development and differentiation of many bone cell types. Recent evidence has demonstrated several ways in which the IGF1 and EFN–EPH signaling pathways interact with and depend upon each other to regulate bone cell function. While much remains to be elucidated, the interaction between these two signaling pathways opens a vast array of new opportunities for investigation into the mechanisms of and potential therapies for skeletal conditions such as osteoporosis and fracture repair.

scholarly journals The Osteocyte: From “Prisoner” to “Orchestrator”

2021 ◽  
Vol 6 (1) ◽  
pp. 28
Author(s):  
Carla Palumbo ◽  
Marzia Ferretti
Keyword(s):  
Bone Remodeling ◽  
Bone Cells ◽  
Bone Matrix ◽  
Bone Cell ◽  
Morphological Aspects ◽  
The Matrix ◽  
Relevant Role ◽  
Mineralized Bone Matrix ◽  
Cell Signaling Pathways

Osteocytes are the most abundant bone cells, entrapped inside the mineralized bone matrix. They derive from osteoblasts through a complex series of morpho-functional modifications; such modifications not only concern the cell shape (from prismatic to dendritic) and location (along the vascular bone surfaces or enclosed inside the lacuno-canalicular cavities, respectively) but also their role in bone processes (secretion/mineralization of preosseous matrix and/or regulation of bone remodeling). Osteocytes are connected with each other by means of different types of junctions, among which the gap junctions enable osteocytes inside the matrix to act in a neuronal-like manner, as a functional syncytium together with the cells placed on the vascular bone surfaces (osteoblasts or bone lining cells), the stromal cells and the endothelial cells, i.e., the bone basic cellular system (BBCS). Within the BBCS, osteocytes can communicate in two ways: by means of volume transmission and wiring transmission, depending on the type of signals (metabolic or mechanical, respectively) received and/or to be forwarded. The capability of osteocytes in maintaining skeletal and mineral homeostasis is due to the fact that it acts as a mechano-sensor, able to transduce mechanical strains into biological signals and to trigger/modulate the bone remodeling, also because of the relevant role of sclerostin secreted by osteocytes, thus regulating different bone cell signaling pathways. The authors want to emphasize that the present review is centered on the morphological aspects of the osteocytes that clearly explain their functional implications and their role as bone orchestrators.

scholarly journals Targeted Ptpn11 deletion in mice reveals the essential role of SHP2 in osteoblast differentiation and skeletal homeostasis

Bone Research ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Lijun Wang ◽  
Huiliang Yang ◽  
Jiahui Huang ◽  
Shaopeng Pei ◽  
Liyun Wang ◽  
...  
Keyword(s):  
Bone Cells ◽  
Protein Tyrosine Phosphatases ◽  
Osteoblastic Differentiation ◽  
Bone Cell ◽  
Signaling Proteins ◽  
Tubular Bone ◽  
Skeletal Homeostasis ◽  
Underlying Mechanisms ◽  
And Function

AbstractThe maturation and function of osteoblasts (OBs) rely heavily on the reversible phosphorylation of signaling proteins. To date, most of the work in OBs has focused on phosphorylation by tyrosyl kinases, but little has been revealed about dephosphorylation by protein tyrosine phosphatases (PTPases). SHP2 (encoded by PTPN11) is a ubiquitously expressed PTPase. PTPN11 mutations are associated with both bone and cartilage manifestations in patients with Noonan syndrome (NS) and metachondromatosis (MC), although the underlying mechanisms remain elusive. Here, we report that SHP2 deletion in bone gamma-carboxyglutamate protein-expressing (Bglap+) bone cells leads to massive osteopenia in both trabecular and cortical bones due to the failure of bone cell maturation and enhanced osteoclast activity, and its deletion in Bglap+ chondrocytes results in the onset of enchondroma and osteochondroma in aged mice with increased tubular bone length. Mechanistically, SHP2 was found to be required for osteoblastic differentiation by promoting RUNX2/OSTERIX signaling and for the suppression of osteoclastogenesis by inhibiting STAT3-mediated RANKL production by osteoblasts and osteocytes. These findings are likely to explain the compromised skeletal system in NS and MC patients and to inform the development of novel therapeutics to combat skeletal disorders.

scholarly journals Mechanical loading and how it affects bone cells: The role of the osteocyte cytoskeleton in maintaining our skeleton

2012 ◽  
Vol 24 ◽  
pp. 278-291 ◽  
Author(s):  
J Klein-Nulend ◽  
◽  
RG Bacabac ◽  
AD Bakker
Keyword(s):  
Mechanical Loading ◽  
Bone Cells
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