Clopidogrel (Plavix), a P2Y12receptor antagonist, inhibits bone cell function in vitro and decreases trabecular bone in vivo

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.

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

Biochemical Society Transactions ◽

10.1042/bst20200210 ◽

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.

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

Experimental Biology and Medicine ◽

10.1177/153537020322800302 ◽

2003 ◽

Vol 228 (3) ◽

pp. 245-252 ◽

Cited By ~ 72

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.

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

AJP Cell Physiology ◽

10.1152/ajpcell.00328.2021 ◽

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.

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Leptin directly regulates bone cell function in vitro and reduces bone fragility in vivo

Journal of Endocrinology ◽

10.1677/joe.0.1750405 ◽

2002 ◽

Vol 175 (2) ◽

pp. 405-415 ◽

Cited By ~ 316

Author(s):

J Cornish ◽

KE Callon ◽

U Bava ◽

C Lin ◽

D Naot ◽

...

Keyword(s):

Bone Mass ◽

Leptin Receptor ◽

Cell Function ◽

Plate Thickness ◽

Bone Fragility ◽

Bone Cell ◽

Mouse Bone Marrow ◽

High Bone Mass

Fat mass is an important determinant of bone density, but the mechanism of this relationship is uncertain. Leptin, as a circulating peptide of adipocyte origin, is a potential contributor to this relationship. Recently it was shown that intracerebroventricular administration of leptin is associated with bone loss, suggesting that obesity should be associated with low bone mass, the opposite of what is actually found. Since leptin originates in the periphery, an examination of its direct effects on bone is necessary to address this major discrepancy. Leptin (>10(-11) m) increased proliferation of isolated fetal rat osteoblasts comparably with IGF-I, and these cells expressed the signalling form of the leptin receptor. In mouse bone marrow cultures, leptin (>or=10(-11) m) inhibited osteoclastogenesis, but it had no effect on bone resorption in two assays of mature osteoclasts. Systemic administration of leptin to adult male mice (20 injections of 43 micro g/day over 4 weeks) reduced bone fragility (increased work to fracture by 27% and displacement to fracture by 21%, P<0.001). Changes in tibial histomorphometry were not statistically significant apart from an increase in growth plate thickness in animals receiving leptin. Leptin stimulated proliferation of isolated chondrocytes, and these cells also expressed the signalling form of the leptin receptor. It is concluded that the direct bone effects of leptin tend to reduce bone fragility and could contribute to the high bone mass and low fracture rates of obesity. When administered systemically, the direct actions of leptin outweigh its centrally mediated effects on bone, the latter possibly being mediated by leptin's regulation of insulin sensitivity.

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Modulation of Endocannabinoid Tone in Osteoblastic Differentiation of MC3T3-E1 Cells and in Mouse Bone Tissue over Time

Cells ◽

10.3390/cells10051199 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1199

Author(s):

Magdalena Kostrzewa ◽

Ali Mokhtar Mahmoud ◽

Roberta Verde ◽

Federica Scotto di Carlo ◽

Fernando Gianfrancesco ◽

...

Keyword(s):

Osteoblast Differentiation ◽

Cannabinoid Receptors ◽

Bone Growth ◽

Cell Function ◽

Bone Cell ◽

Mature Adult ◽

Age Related ◽

Over Time

Bone is a highly complex and metabolically active tissue undergoing a continuous remodeling process, which endures throughout life. A complex cell-signaling system that plays role in regulating different physiological processes, including bone remodeling, is the endocannabinoid system (ECS). Bone mass expresses CB1 and CB2 cannabinoid receptors and enzymatic machinery responsible for the metabolism of their endogenous ligands, endocannabinoids (AEA and 2-AG). Exogenous AEA is reported to increase the early phase of human osteoblast differentiation in vitro. However, regarding this cell context little is known about how endocannabinoids and endocannabinoid-related N-acylethanolamines like PEA and OEA are modulated, in vitro, during cell differentiation and, in vivo, over time up to adulthood. Here we characterized the endocannabinoid tone during the different phases of the osteoblast differentiation process in MC3T3-E1 cells, and we measured endocannabinoid levels in mouse femurs at life cycle stages characterized by highly active bone growth (i.e., of juvenile, young adult, and mature adult bone). Endocannabinoid tone was significantly altered during osteoblast differentiation, with substantial OEA increment, decline in 2-AG and AEA, and consistent modulation of their metabolic enzymes in maturing and mineralized MC3T3-E1 cells. Similarly, in femurs, we found substantial, age-related, decline in 2-AG, OEA, and PEA. These findings can expand existing knowledge underlying physiological bone cell function and contribute to therapeutic strategies for preventing bone-related metabolic changes accruing through lifespan.

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Analysis of trabecular bone structure demonstrates new mechanisms of bone cell function in primary hyperparathyroidism

Acta Endocrinologica ◽

10.1530/acta.0.117s083 ◽

1988 ◽

Vol 117 (4_Suppl) ◽

pp. S83 ◽

Cited By ~ 1

Author(s):

M. VOGEL ◽

M. HAHN ◽

G. DELLING

Keyword(s):

Primary Hyperparathyroidism ◽

Trabecular Bone ◽

Cell Function ◽

Bone Structure ◽

Bone Cell ◽

Trabecular Bone Structure

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A cloned cell line mediating natural killer cell function inhibits immunoglobulin secretion.

Journal of Experimental Medicine ◽

10.1084/jem.156.2.658 ◽

1982 ◽

Vol 156 (2) ◽

pp. 658-663 ◽

Cited By ~ 53

Author(s):

G Nabel ◽

W J Allard ◽

H Cantor

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Cell Line ◽

B Lymphocytes ◽

Cell Function ◽

Killer Cell ◽

Major Histocompatibility Complex Gene ◽

Cell Surface Antigens

We previously described a cloned cell line that combines information for a unique display of cell surface antigens and specialized function similar to activated natural killer (NK) cells. In addition to conventional cellular targets such as the YAC-1 and MBL-2 lymphomas, this cloned line also lysed lipopolysaccharide-activated B lymphocytes. To determine whether some NK cells can inhibit B cell function, we tested the ability of NK-like clones to suppress Ig secretion in vitro and in vivo. These cloned cells suppressed Ig secretion when they constituted as few as 0.2% of the total cell population and inhibition did not require identity at the H-2 locus. We suggest that some NK cells might recognize non-major histocompatibility complex gene products on activated B lymphocytes and lyse these cells, and this might represent a fundamental cell-cell interaction that regulates antibody secretion by activated B cells.

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Identification of the immunophilins capable of mediating inhibition of signal transduction by cyclosporin A and FK506: roles of calcineurin binding and cellular location

Molecular and Cellular Biology ◽

10.1128/mcb.13.8.4760-4769.1993 ◽

1993 ◽

Vol 13 (8) ◽

pp. 4760-4769

Author(s):

R J Bram ◽

D T Hung ◽

P K Martin ◽

S L Schreiber ◽

G R Crabtree

Keyword(s):

Signal Transduction ◽

T Cell ◽

Cyclosporin A ◽

Cell Function ◽

Inhibitory Effects ◽

Gene Deletions ◽

Cyclophilin B ◽

Intracellular Vesicles

The immunosuppressants cyclosporin A (CsA) and FK506 appear to block T-cell function by inhibiting the calcium-regulated phosphatase calcineurin. While multiple distinct intracellular receptors for these drugs (cyclophilins and FKBPs, collectively immunophilins) have been characterized, the functionally active ones have not been discerned. We found that overexpression of cyclophilin A or B or FKBP12 increased T-cell sensitivity to CsA or FK506, respectively, demonstrating that they are able to mediate the inhibitory effects of their respective immunosuppressants in vivo. In contrast, cyclophilin C, FKBP13, and FKBP25 had no effect. Direct comparison of the Ki of each drug-immunophilin complex for calcineurin in vitro revealed that although calcineurin binding was clearly necessary, it was not sufficient to explain the in vivo activity of the immunophilin. Subcellular localization was shown also to play a role, since gene deletions of cyclophilins B and C which changed their intracellular locations altered their activities significantly. Cyclophilin B has been shown previously to be located within calcium-containing intracellular vesicles; its ability to mediate CsA inhibition implies that certain components of the signal transduction machinery are also spatially restricted within the cell.

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