High Bone Mass in Mice Lacking Cx37 Because of Defective Osteoclast Differentiation

Pacheco‐Costa, Rafael; Hassan, Iraj; Reginato, Rejane Daniele; Davis, Hannah M.; Bruzzaniti, Angela; Allen, Matthew R.; Plotkin, Lilian I.

doi:10.1074/jbc.m113.529735

Cited by 55 publications

(78 citation statements)

References 54 publications

(64 reference statements)

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“…Total RNA was isolated and purified using TRIzol (Invitrogen), as published (Pacheco‐Costa et al ., 2014). Reverse transcription was performed using a high‐capacity cDNA kit (Applied Biosystems, Foster City, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…The conditioned medium from MLO‐Y4 osteocytic cells silenced or not for Cx43 was collected after 24 h‐culture and then concentrated 4× using centricon filters (10 kDa cutoff) (EDM Millipore). Media was diluted 1:4 and added to 48‐well plate containing 2 × 10 5 nonadherent cells cm −2 with 40 ng mL −1 RANKL and 20 ng mL −1 M‐CSF (Pacheco‐Costa et al ., 2014). Growing medium that had not been in contact with the cells was used as control.…”

Section: Methodsmentioning

confidence: 99%

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Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging

et al. 2017

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SummarySkeletal aging results in apoptosis of osteocytes, cells embedded in bone that control the generation/function of bone forming and resorbing cells. Aging also decreases connexin43 (Cx43) expression in bone; and osteocytic Cx43 deletion partially mimics the skeletal phenotype of old mice. Particularly, aging and Cx43 deletion increase osteocyte apoptosis, and osteoclast number and bone resorption on endocortical bone surfaces. We examined herein the molecular signaling events responsible for osteocyte apoptosis and osteoclast recruitment triggered by aging and Cx43 deficiency. Cx43‐silenced MLO‐Y4 osteocytic (Cx43def) cells undergo spontaneous cell death in culture through caspase‐3 activation and exhibit increased levels of apoptosis‐related genes, and only transfection of Cx43 constructs able to form gap junction channels reverses Cx43def cell death. Cx43def cells and bones from old mice exhibit reduced levels of the pro‐survival microRNA miR21 and, consistently, increased levels of the miR21 target phosphatase and tensin homolog (PTEN) and reduced phosphorylated Akt, whereas PTEN inhibition reduces Cx43def cell apoptosis. miR21 reduction is sufficient to induce apoptosis of Cx43‐expressing cells and miR21 deletion in miR21fl/fl bones increases apoptosis‐related gene expression, whereas a miR21 mimic prevents Cx43def cell apoptosis, demonstrating that miR21 lies downstream of Cx43. Cx43def cells release more osteoclastogenic cytokines [receptor activator of NFκB ligand (RANKL)/high‐mobility group box‐1 (HMGB1)], and caspase‐3 inhibition prevents RANKL/HMGB1 release and the increased osteoclastogenesis induced by conditioned media from Cx43def cells, which is blocked by antagonizing HMGB1‐RAGE interaction. These findings identify a novel Cx43/miR21/HMGB1/RANKL pathway involved in preventing osteocyte apoptosis that also controls osteoclast formation/recruitment and is impaired with aging.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging

et al. 2017

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“…The left femurs and lumbar (L5) vertebrae obtained from 4-monthold male mice were tested via three-point bending and compression, respectively, following previously published protocols [21]. Briefly, bones were brought to room temperature slowly (~2 h) in a saline bath, and loaded to failure at 2 mm/min with force versus displacement data collected at 10 Hz using a servo-hydraulic test system (Test Resources).…”

Section: Biomechanical Testingmentioning

confidence: 99%

Deletion of Nrf2 reduces skeletal mechanical properties and decreases load-driven bone formation

Sun

Corry

et al. 2015

Bone

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“…Vertebral bodies were loaded at a rate of 0.5 mm/min until failure (100P225 Modular Test Machine) as described. (41,42) Structural properties were obtained from the load/displacement curves and material-level properties were calculated using published equations to normalize to vertebral height, cross-sectional area, and bone volume. (43) Ex vivo cultures Femoral and tibial long bones were harvested from WT and Sost -/-mice, and then maintained in a-MEM containing 10% FBS and 1% penicillin/streptomycin for 24 hours.…”

Section: Mechanical Testingmentioning

confidence: 99%

Protection From Glucocorticoid-Induced Osteoporosis by Anti-Catabolic Signaling in the Absence of Sost/Sclerostin

Sato

Cregor

Delgado‐Calle

et al. 2016

Journal of Bone and Mineral Research

105

108

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Excess of glucocorticoids, either due to disease or iatrogenic, increases bone resorption and decreases bone formation and is a leading cause of osteoporosis and bone fractures worldwide. Improved therapeutic strategies are sorely needed. We investigated whether activating Wnt/b-catenin signaling protects against the skeletal actions of glucocorticoids, using female mice lacking the Wnt/b-catenin antagonist and bone formation inhibitor Sost. Glucocorticoids decreased the mass, deteriorated the microarchitecture, and reduced the structural and material strength of bone in wild-type (WT), but not in Sost -/-mice. The high bone mass exhibited by Sost -/-mice is due to increased bone formation with unchanged resorption. However, unexpectedly, preservation of bone mass and strength in Sost -/-mice was due to prevention of glucocorticoid-induced bone resorption and not to restoration of bone formation. In WT mice, glucocorticoids increased the expression of Sost and the number of sclerostin-positive osteocytes, and altered the molecular signature of the Wnt/b-catenin pathway by decreasing the expression of genes associated with both anticatabolism, including osteoprotegerin (OPG), and anabolism/survival, such as cyclin D1. In contrast in Sost -/-mice, glucocorticoids did not decrease OPG but still reduced cyclin D1. Thus, in the context of glucocorticoid excess, activation of Wnt/b-catenin signaling by Sost/sclerostin deficiency sustains bone integrity by opposing bone catabolism despite markedly reduced bone formation and increased apoptosis. This crosstalk between glucocorticoids and Wnt/b-catenin signaling could be exploited therapeutically to halt resorption and bone loss induced by glucocorticoids and to inhibit the exaggerated bone formation in diseases of unwanted hyperactivation of Wnt/b-catenin signaling.

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High Bone Mass in Mice Lacking Cx37 Because of Defective Osteoclast Differentiation

Cited by 55 publications

References 54 publications

Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging

Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging

Deletion of Nrf2 reduces skeletal mechanical properties and decreases load-driven bone formation

Protection From Glucocorticoid-Induced Osteoporosis by Anti-Catabolic Signaling in the Absence of Sost/Sclerostin

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