RANKL and OPG activity is regulated by injury size in networks of osteocyte-like cells

Mulcahy, Lauren; Taylor, David; Lee, T. Clive; Duffy, Garry P.

doi:10.1016/j.bone.2010.09.014

Cited by 65 publications

(57 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This lends considerable weight to our "scissors" hypothesis: if these ruptures can be detected by the cell, then their number provides a very convenient way to assess the severity of the crack and the need to repair it. Evidence that ruptures to the cell network can initiate cell signalling pathways has already been provided by our recent work on cell networks cultured in vitro in 3D gel matrices (Mulcahy et al, 2011).…”

Section: Discussionmentioning

confidence: 92%

Rupture of osteocyte processes across microcracks: the effect of crack length and stress

Dooley

Tisbo

Lee

et al. 2011

Biomech Model Mechanobiol

Self Cite

View full text Add to dashboard Cite

Bone cells are connected to one another in a network, via their dendritic cellular processes. Previously, we hypothesised that these processes could be ruptured by microcracks. We proposed this as a mechanism by which osteoctyes could detect the presence of microcracks. In order for this mechanism to be effective, the number of ruptured processes would have to increase with microcrack length and also with the applied cyclic stress applied. This paper presents for the first time experimental data which shows that this is indeed the case. We examined samples of bovine, ovine and murine bone ex vivo and observed processes passing across crack faces: some were still intact whilst others had ruptured. The number of intact processes per unit crack length decreased significantly with increasing crack length, and also decreased in samples which had been tested in vitro at higher stress levels. A theoretical model which we had developed previously was able to predict the overall magnitude and general trends in the experimental data. This work has provided further support for our "scissors" model which proposes that microcracks can be detected because they disturb the osteocyte network, specifically by rupturing cellular processes where they pass across the crack faces. AbstractBone cells are connected to one another in a network, via their dendritic cellular processes. Previously, we hypothesised that these processes could be ruptured by microcracks. We proposed this as a mechanism by which osteoctyes could detect the presence of microcracks. In order for this mechanism to be effective, the number of ruptured processes would have to increase with microcrack length and also with the applied cyclic stress applied. This paper presents for the first time experimental data which shows that this is indeed the case. We examined samples of bovine, ovine and murine bone ex vivo and observed processes passing across crack faces: some were still intact whilst others had ruptured. The number of intact processes per unit crack length decreased significantly with increasing crack length, and also decreased in samples which had been tested in vitro at higher stress levels. A theoretical model which we had developed previously was able to predict the overall magnitude and general trends in the experimental data. This work has provided further support for our "scissors" model which proposes that microcracks can be detected because they disturb the osteocyte network, specifically by rupturing cellular processes where they pass across the crack faces.

show abstract

Section: Discussionmentioning

confidence: 92%

Rupture of osteocyte processes across microcracks: the effect of crack length and stress

Dooley

Tisbo

Lee

et al. 2011

Biomech Model Mechanobiol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Owing to their position within the bone and their complex communication network, it has been widely accepted that osteocytes are sensory cells that can control and regulate mineralization in response to mechanical stimuli or tissue damage [33,39,40]. A recent study examined whether cells, having undergone mechanical damage in the form of cell process rupture, emitted biochemical signals to neighbouring cells to initiate a response to damage [41]. It was demonstrated that when MLO-Y4 cell networks were subjected to mechanical damage (160-800 mm planar, crack-like defects), altered production of cytokines known to regulate bone remodelling (receptor activator of NFkB ligand, osteoprotegerin) occurred depending on the extent of damage and recovery time following application of injury [41].…”

Section: Discussionmentioning

confidence: 99%

“…A recent study examined whether cells, having undergone mechanical damage in the form of cell process rupture, emitted biochemical signals to neighbouring cells to initiate a response to damage [41]. It was demonstrated that when MLO-Y4 cell networks were subjected to mechanical damage (160-800 mm planar, crack-like defects), altered production of cytokines known to regulate bone remodelling (receptor activator of NFkB ligand, osteoprotegerin) occurred depending on the extent of damage and recovery time following application of injury [41]. This study proposed that in spite of an injured cell's impaired viability, microcracks were detected by surrounding non-injured cells, which can signal to initiate the repair response in neighbouring cells [41].…”

Section: Discussionmentioning

confidence: 99%

Heat-shock-induced cellular responses to temperature elevations occurring during orthopaedic cutting

Duffy

Haugh

Tallon

et al. 2012

J. R. Soc. Interface.

View full text Add to dashboard Cite

Severe heat-shock to bone cells caused during orthopaedic procedures can result in thermal damage, leading to cell death and initiating bone resorption. By contrast, mild heat-shock has been proposed to induce bone regeneration. In this study, bone cells are exposed to heat-shock for short durations occurring during surgical cutting. Cellular viability, necrosis and apoptosis are investigated immediately after heat-shock and following recovery of 12, 24 h and 4 days, in osteocyte-like MLO-Y4 and osteoblast-like MC3T3-E1 cells, using flow cytometry. The regeneration capacity of heat-shocked Balb/c mesenchymal stem cells (MSCs) and MC3T3-E1s has been investigated following 7 and 14 day's recovery, by quantifying proliferation, differentiation and mineralization. An immediate necrotic response to heat-shock was shown in cells exposed to elevated temperatures (458C, 478C and most severe at 608C). A longer-term apoptotic response is induced in MLO-Y4s and, to a lesser extent, in MC3T3-E1s. Heat-shock-induced differentiation and mineralization by MSCs. These findings indicate that heat-shock is more likely to induce apoptosis in osteocytes than osteoblasts, which might reflect their role as sensors detecting and communicating damage within bone. Furthermore, it is shown for the first time that mild heat-shock (less than equal to 478C) for durations occurring during surgical cutting can positively enhance osseointegration by osteoprogenitors.

show abstract

“…In the case of osteocytes, the osteoclastic response required to engulf apoptotic cells is complex as they are buried deep within the mineralized bone tissue and are difficult to access. Therefore, it may be necessary for apoptotic osteocytes to signal neighbouring healthy cells, which in turn signal to activate nearby pre-osteoclasts [14,18,[34][35][36][37]. A recent study demonstrated that, although osteocyte apoptosis triggers the bone remodelling response to microdamage, the neighbouring non-apoptotic osteocytes are the major source of pro-osteoclastogenic signals [14,18].…”

Section: Discussionmentioning

confidence: 99%

Thermally induced osteocyte damage initiates pro-osteoclastogenic gene expression in vivo

Duffy

Tallon

Cheung

et al. 2016

J. R. Soc. Interface.

View full text Add to dashboard Cite

Bone is often subject to harsh temperatures during orthopaedic procedures resulting in thermally induced bone damage, which may affect the healing response. Postsurgical healing of bone is essential to the success of surgery, therefore, an understanding of the thermally induced responses of bone cells to clinically relevant temperatures in vivo is required. Osteocytes have been shown to be integrally involved in the bone remodelling cascade, via apoptosis, in micro-damage systems. However, it is unknown whether this relationship is similar following thermal damage. Sprague-Dawley rat tibia were exposed to clinically relevant temperatures (478C or 608C) to investigate the role of osteocytes in modulating remodelling related factors. Immunohistochemistry was used to quantify osteocyte thermal damage (activated caspase-3). Thermally induced pro-osteoclastogenic genes (Rankl, Opg and M-csf ), in addition to genes known to mediate osteoblast and osteoclast differentiation via prostaglandin production (Cox2), vascularization (Vegf ) and inflammatory (Il1a) responses, were investigated using gene expression analysis. The results demonstrate that heat-treatment induced significant bone tissue and cellular damage. Pro-osteoclastogenic genes were upregulated depending on the amount of temperature elevation compared with the control. Taken together, the results of this study demonstrate the in vivo effect of thermally induced osteocyte damage on the gene expression profile.

show abstract

RANKL and OPG activity is regulated by injury size in networks of osteocyte-like cells

Cited by 65 publications

References 38 publications

Rupture of osteocyte processes across microcracks: the effect of crack length and stress

Rupture of osteocyte processes across microcracks: the effect of crack length and stress

Heat-shock-induced cellular responses to temperature elevations occurring during orthopaedic cutting

Thermally induced osteocyte damage initiates pro-osteoclastogenic gene expression in vivo

Contact Info

Product

Resources

About