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Cell autonomous requirement of connexin 43 for osteocyte survival: consequences for endocortical resorption and periosteal bone formation.

ABSTRACT: Connexin 43 (Cx43) mediates osteocyte communication with other cells and with the extracellular milieu and regulates osteoblastic cell signaling and gene expression. We now report that mice lacking Cx43 in osteoblasts/osteocytes or only in osteocytes (Cx43(?Ot) mice) exhibit increased osteocyte apoptosis, endocortical resorption, and periosteal bone formation, resulting in higher marrow cavity and total tissue areas measured at the femoral mid-diaphysis. Blockade of resorption reversed the increased marrow cavity but not total tissue area, demonstrating that endocortical resorption and periosteal apposition are independently regulated. Anatomical mapping of apoptotic osteocytes, osteocytic protein expression, and resorption and formation suggests that Cx43 controls osteoclast and osteoblast activity by regulating osteoprotegerin and sclerostin levels, respectively, in osteocytes located in specific areas of the cortex. Whereas empty lacunae and living osteocytes lacking osteoprotegerin were distributed throughout cortical bone in Cx43(?Ot) mice, apoptotic osteocytes were preferentially located in areas containing osteoclasts, suggesting that osteoclast recruitment requires active signaling from dying osteocytes. Furthermore, Cx43 deletion in cultured osteocytic cells resulted in increased apoptosis and decreased osteoprotegerin expression. Thus, Cx43 is essential in a cell-autonomous fashion in vivo and in vitro for osteocyte survival and for controlling the expression of osteocytic genes that affect osteoclast and osteoblast function.

SUBMITTER: Bivi N

PROVIDER: S-EPMC3271138 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Cell autonomous requirement of connexin 43 for osteocyte survival: consequences for endocortical resorption and periosteal bone formation.

Bivi Nicoletta N Condon Keith W KW Allen Matthew R MR Farlow Nathan N Passeri Giovanni G Brun Lucas R LR Rhee Yumie Y Bellido Teresita T Plotkin Lilian I LI

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20120201 2

Connexin 43 (Cx43) mediates osteocyte communication with other cells and with the extracellular milieu and regulates osteoblastic cell signaling and gene expression. We now report that mice lacking Cx43 in osteoblasts/osteocytes or only in osteocytes (Cx43(ΔOt) mice) exhibit increased osteocyte apoptosis, endocortical resorption, and periosteal bone formation, resulting in higher marrow cavity and total tissue areas measured at the femoral mid-diaphysis. Blockade of resorption reversed the incre ...[more]

PMID: 22028311

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Project description:Osteocyte apoptosis has been linked to bone resorption resulting from estrogen depletion and other resorptive stimuli; however, precise spatial and temporal relationships between the two events have not been clearly established. The purpose of this study was to characterize the patterns of osteocyte apoptosis in relation to bone resorption following ovariectomy to test whether osteocyte apoptosis occurs preferentially in areas known to activate resorption. Moreover, we report that osteocyte apoptosis is necessary to initiate endocortical remodeling in response to estrogen withdrawal.Adult female C57BL/6J mice (17 weeks old) underwent either bilateral ovariectomy (OVX), or sham surgery (SHAM) and were euthanized on days 3, 7, 14, or 21 days after OVX. Diaphyseal cross-sections were stained by immunohistochemistry for activated caspase-3 as a marker of apoptosis. The percentages of caspase-positive stained osteocytes (Casp+Ot.) were measured along major and minor anatomical axes around the femoral diaphysis to evaluate the distribution of osteocyte apoptosis after estrogen loss; resorption surface was measured at the adjacent endocortical regions. In a second study to test whether osteocyte apoptosis plays a regulatory role in the initiation of bone resorption, a group of OVX mice received the pan-caspase inhibitor, QVDOPh, to inhibit osteocyte apoptosis. Remaining experimental and sham groups received either QVD or Vehicle.OVX increased osteocyte apoptosis in a non-uniform distribution throughout the femoral diaphyses. Increases in Casp+osteocytes were predominantly located in the posterior diaphyseal cortex. Here, the number of apoptotic osteocytes 4- to 7-fold higher than sham controls (p<0.005) by day 3 post-OVX and remained elevated. Increases in resorption post-OVX also occurred along the posterior endocortical surface overlying the region of osteocyte apoptosis, but these increases occurred only at 14 and 21 days post-OVX (p<0.002) well after the increases in osteocyte apoptosis. Treatment with QVD in OVX animals suppressed osteocyte apoptosis, with levels in QVD-treated samples equivalent to baseline. Moreover, the increases in osteoclastic resorption normally observed after estrogen loss did not occur in OVX mice treated with QVD.The results of this study demonstrate that osteocyte apoptosis following estrogen loss occur regionally, rather than uniformly throughout the cortex. We also showed that estrogen loss increased osteocyte apoptosis. Apoptotic osteocytes were overwhelmingly localized within the posterior cortical region, the location where endocortical resorption was subsequently activated in ovariectomized mice. Finally, the increases in osteoclastic resorption normally observed after estrogen withdrawal did not occur in the absence of osteocyte apoptosis indicating that this apoptosis is necessary to activate endocortical remodeling following estrogen loss.

Project description:The capacity of bone to optimize its structure in response to mechanical loads has been widely observed. The mechanical load acting on a bone at the macroscopic level influences the bone cells, particularly osteocytes within the lacunae canalicular network (LCN). Osteocytes are responsive to a range of physical signals, including strain, interstitial fluid flow, and pore pressure. However, physiological tissue strain is known to be typically smaller than that required to directly induce bone formation. On the other hand, as per evidence provided by this study from the literature, models based on fluid flow alone cannot simultaneously predict bone formation at both the periosteal and endocortical surfaces. This suggests that another component of the osteocyte's mechanical environment, such as pore pressure, may play an essential role in bone adaptation, either alone or in combination with other stimuli, such as tissue strain and/or interstitial fluid flow. In vitro experiments have also confirmed that osteocytes respond to cyclic pore pressure and, thus, have a mechanism to sense the pressure, possibly because of its viscoelasticity. In this work, dissipation energy density, being irreversible work done per unit volume, has been successfully used as a greater stimulus to incorporate all of the parameters of mechanical environments of the LCN, such as waveforms of both fluid velocity and pore pressure, number of loading cycles. Mineral Apposition Rate (MAR) has also been mathematically derived to be proportional to the square root of the dissipation energy density minus its reference value. A hypothesis is accordingly proposed and successfully tested/validated for both endocortical and periosteal surfaces with respect to an in-vivo study on mouse tibia available in the literature. The constant of proportionality and the reference/threshold value of the dissipation energy density are determined through a nonlinear curve fitting. The mathematical/computational method thus developed is then successfully used to predict MAR at both endocortical and periosteal surfaces induced by a different loading condition. Computational implementation of the mathematical model has been done through a poroelastic finite element analysis of bone, where bone is assumed to be porous and filled with fluid, with a boundary condition that the periosteum is impermeable to the fluid and the endosteal surface maintains a reference zero pressure. This work also provides evidence for these assumptions to be true based on the state-of-the-art literature on related experimental studies. The currently developed model shows that the bone uses these conditions (assumptions) to its advantage, as the greater stimulus, i.e., the dissipation energy due to both fluid flow and pore pressure, are of a similar order at both the surfaces, and hence osteogenesis of the same order at both the surfaces. As a bottom line, the resulting model is the first of its kind as it has been able to correctly predict MAR at both endocortical and periosteal surfaces. This study thus significantly advances the modeling of cortical bone adaptation to exogenous mechanical loading.

Dataset Information

Cell autonomous requirement of connexin 43 for osteocyte survival: consequences for endocortical resorption and periosteal bone formation.

Publications

Cell autonomous requirement of connexin 43 for osteocyte survival: consequences for endocortical resorption and periosteal bone formation.

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