Osteocyte apoptosis is required for production of osteoclastogenic signals following bone fatigue in vivo

Kennedy, Oran D.; Laudier, Damien M.; Majeska, Robert J.; Sun, Hui; Schaffler, Mitchell B.

doi:10.1016/j.bone.2014.03.049

Cited by 133 publications

(146 citation statements)

References 49 publications

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“…Interface 13: 20160337 tissue and apoptosis of the heat-treated osteocytes themselves occurs. This is in agreement with Kennedy et al, who report a similar response after micro-crack induced apoptosis [14,18]. They report that although osteocyte apoptosis triggers the bone remodelling response to micro-damage, the neighbouring non-apoptotic cells are the major source of pro-osteoclastogenic signals [18].…”

Section: Discussionsupporting

confidence: 88%

“…This is in agreement with Kennedy et al, who report a similar response after micro-crack induced apoptosis [14,18]. They report that although osteocyte apoptosis triggers the bone remodelling response to micro-damage, the neighbouring non-apoptotic cells are the major source of pro-osteoclastogenic signals [18]. When the bone tissue was exposed to 608C, a significantly increased area of non-viable tissue and apoptotic osteocytes was observed.…”

Section: Discussionsupporting

confidence: 88%

“…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%

“…Osteocyte apoptosis was quantified by immunohistochemical staining for cleaved caspase-3. Samples from the heattreated (478C (n ¼ 6) or 608C (n ¼ 6)) and control limbs were treated for 30 min with 20 mg ml 21 of proteinase K in TE buffer for antigen retrieval, and then blocked for 30 min to prevent nonspecific staining (Protein Block, Dako Diagnostics IRL Ltd) [18]. Sections were then incubated at 48C overnight with a 1 : 100 dilution of rabbit antibody against cleaved caspase-3 (#9661, Cell Signaling Technologies, Carpinteria, CA, USA) followed by 1 h incubation with a 1 : 700 dilution of Alexa Fluor 488-conjugated 28 antibody (A11029, Invitrogen, CA, USA).…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Surgically induced damage and fatigue-induced micro-damage to bone are well-known initiators of osteocyte apoptosis [13][14][15][16][17]. More recently, it has been shown that micro-damage induces localized osteocyte apoptosis, which causes upregulation of the pro-osteoclastogenic factor Rankl together with a downregulation of the Rankl inhibitor Opg by nearby non-injured cells, initiating the bone remodelling process to repair damaged tissues [13][14][15]18]. It is intriguing to speculate that thermally induced damage might activate bone remodelling in a similar fashion.…”

Section: Introductionmentioning

confidence: 99%

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

Duffy

Tallon

Cheung

et al. 2016

J. R. Soc. Interface.

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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.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Immunohistochemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Duffy

Tallon

Cheung

et al. 2016

J. R. Soc. Interface.

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Estrogen inhibits starvation‐induced apoptosis in osteocytes by a redox‐independent process involving association of JNK and glutathione S‐transferase P1‐1

et al. 2017

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Estrogen deficiency causes bone loss as a result of microdamage, oxidative stress, and osteocyte apoptosis. A relationship between oxidative stress‐induced apoptosis, c‐Jun N‐terminal kinase (JNK) activation, and expression of factors involved in bone remodeling has been demonstrated in osteocytes. However, the molecular regulation of these events in osteocytes treated with 17β‐estradiol (17β‐E2) remains unexplored. The MLO‐Y4 murine osteocyte‐like cell line was used as a model to study starvation‐induced apoptosis and ROS production during 17β‐E2 treatment. Expression of glutathione S‐transferase P1‐1 (GSTP1‐1), receptor activator kB ligand (RANKL), osteoprotegerin (OPG), sclerostin, and kinases activation were measured by western blot. In addition, the GSTP1‐1/JNK association was assessed by immunoprecipitation, and GSTP1‐1 involvement in the osteocyte response to 17β‐E2 was detected by specific siRNA transfection. 17β‐E2 prevents starvation‐induced apoptosis (DNA fragmentation and caspase activation), the increase in sclerostin expression and the RANKL/OPG ratio, which are all related to JNK activation due to oxidative stress in osteocytes. This occurs through GSTP1‐1 overexpression, which can inhibit JNK activation by formation of a GSTP1‐1/JNK complex. No early antioxidant action of 17β‐E2 has been found but the estrogen effect is similar to N‐acetylcysteine which, by increasing the intracellular redox state, maintains JNK bound to GSTP1‐1. Thus, the antiapoptotic and osteogenic effect of 17β‐E2 in MLO‐Y4 occurs by a redox‐independent process involving GSTP1‐1/JNK association. This study clarifies at molecular level the effect of 17β‐E2 on osteocyte activity and identifies a possible role of GSTP1‐1 and JNK activity in bone remodeling and repair mechanisms.

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Blueberry juice protects osteocytes and bone precursor cells against oxidative stress partly through SIRT1

et al. 2019

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Oxidative stress and abnormal osteocyte apoptosis are often related to dysregulation of bone turnover and chronic bone loss, and so fruit and vegetables with high antioxidant potential may play an important role in the prevention and/or management of osteoporosis. Osteocytes are the main regulators of bone remodelling. For the first time, we demonstrate here that blueberry juice ( BJ ), obtained from Vaccinium myrtillus , rich in polyphenols, shows antioxidant and antiosteoclastogenic properties in MLO ‐Y4 osteocytes. We report that BJ prevents oxidative stress‐induced apoptosis and reverses the increase in receptor activator of nuclear factor κB ligand and sclerostin expression, crucial factors for osteoclast activation and bone resorption. BJ is also able to prevent oxidative stress‐induced cell cytotoxicity in bone marrow mesenchymal stromal cells ( MSC s), which are considered to be an important tool for cell therapy in bone disorders. No significant difference in preventing these events was observed between BJ and blueberry dry extract containing equal amounts of total soluble polyphenols. We have also shown that blueberry acts as both an antioxidant and an activator of sirtuin type 1, a class III histone deacetylase involved in cell death regulation and considered a molecular target for blocking bone resorption without affecting osteoclast survival. Overall, these novel data obtained in osteocytes and MSC s may help us clarify the mechanisms by which blueberry counteracts oxidative stress‐induced damage in bone remodelling and osteogenesis at the cellular and molecular level. Our findings are consistent with the reported beneficial effects of blueberry on bone tissue reported in animal studies, which suggest that blueberry may be a useful supplement for the prevention and/or management of osteoporosis and osteogenic process.

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Osteocyte apoptosis is required for production of osteoclastogenic signals following bone fatigue in vivo

Cited by 133 publications

References 49 publications

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

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

Estrogen inhibits starvation‐induced apoptosis in osteocytes by a redox‐independent process involving association of JNK and glutathione S‐transferase P1‐1

Blueberry juice protects osteocytes and bone precursor cells against oxidative stress partly through SIRT1

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