Abstract
Aseptic loosening is the devastating long term complication of total hip arthroplasty and orthopedic implant debris has been shown to trigger an intense inflammatory reaction leading to resorption of the bone matrix. Inflammatory cytokines, such as tumor necrosis factor-α (TNFα), have been implicated in this process and osteocytes may play a role in its production. We previously demonstrated that cobalt-chromium-molybdenum (CoCrMo) particles upregulate TNFα production by MLO-Y4 osteocytes in vitro, but the underlying mechanism has not been elucidated. Based on previous studies by others, we hypothesized that the calcineurin-nuclear factor of activated T cells (NFAT) pathway mediates CoCrMo particle-induced TNFα production in MLO-Y4 osteocytes. MLO-Y4 osteocytes exposed to CoCrMo particle treatment resulted in a rapid and significant increase in calcineurin activity. We also demonstrate that CoCrMo particle-induced upregulation of TNFα is reduced to control levels with calcineurin-NFAT inhibitors and this was also confirmed at mRNA level. Moreover, we demonstrate the localization of NFATs in MLO-Y4 osteocytes and that NFAT1 and 2 translocate to the nucleus upon CoCrMo particle treatment. Our results suggest that calcineurin-NFAT signaling is involved in TNFα production by MLO-Y4 osteocytes after CoCrMo particle treatment.
| Original language | English |
|---|---|
| Pages (from-to) | 1867-1873 |
| Number of pages | 7 |
| Journal | Journal of Orthopaedic Research |
| Volume | 29 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - 2011 Dec |
| Externally published | Yes |
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Keywords
- calcineurin
- CoCrMo particles
- MLO-Y4 osteocytes
- nuclear factor of activated T cells (NFAT)
- tumor necrosis factor-α (TNFα)
ASJC Scopus subject areas
- Orthopedics and Sports Medicine
Cite this
Calcineurin/nuclear factor of activated T cells (NFAT) signaling in cobalt-chromium-molybdenum (CoCrMo) particles-induced tumor necrosis factor-α (TNFα) secretion in MLO-Y4 osteocytes. / Orhue, Vbenosawemwinghaye; Kanaji, Arihiko; Caicedo, Marco S.; Virdi, Amarjit S.; Sumner, Dale R.; Hallab, Nadim J.; Jahr, Holger; Sena, Kotaro.
In: Journal of Orthopaedic Research, Vol. 29, No. 12, 12.2011, p. 1867-1873.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Calcineurin/nuclear factor of activated T cells (NFAT) signaling in cobalt-chromium-molybdenum (CoCrMo) particles-induced tumor necrosis factor-α (TNFα) secretion in MLO-Y4 osteocytes
AU - Orhue, Vbenosawemwinghaye
AU - Kanaji, Arihiko
AU - Caicedo, Marco S.
AU - Virdi, Amarjit S.
AU - Sumner, Dale R.
AU - Hallab, Nadim J.
AU - Jahr, Holger
AU - Sena, Kotaro
PY - 2011/12
Y1 - 2011/12
N2 - Aseptic loosening is the devastating long term complication of total hip arthroplasty and orthopedic implant debris has been shown to trigger an intense inflammatory reaction leading to resorption of the bone matrix. Inflammatory cytokines, such as tumor necrosis factor-α (TNFα), have been implicated in this process and osteocytes may play a role in its production. We previously demonstrated that cobalt-chromium-molybdenum (CoCrMo) particles upregulate TNFα production by MLO-Y4 osteocytes in vitro, but the underlying mechanism has not been elucidated. Based on previous studies by others, we hypothesized that the calcineurin-nuclear factor of activated T cells (NFAT) pathway mediates CoCrMo particle-induced TNFα production in MLO-Y4 osteocytes. MLO-Y4 osteocytes exposed to CoCrMo particle treatment resulted in a rapid and significant increase in calcineurin activity. We also demonstrate that CoCrMo particle-induced upregulation of TNFα is reduced to control levels with calcineurin-NFAT inhibitors and this was also confirmed at mRNA level. Moreover, we demonstrate the localization of NFATs in MLO-Y4 osteocytes and that NFAT1 and 2 translocate to the nucleus upon CoCrMo particle treatment. Our results suggest that calcineurin-NFAT signaling is involved in TNFα production by MLO-Y4 osteocytes after CoCrMo particle treatment.
AB - Aseptic loosening is the devastating long term complication of total hip arthroplasty and orthopedic implant debris has been shown to trigger an intense inflammatory reaction leading to resorption of the bone matrix. Inflammatory cytokines, such as tumor necrosis factor-α (TNFα), have been implicated in this process and osteocytes may play a role in its production. We previously demonstrated that cobalt-chromium-molybdenum (CoCrMo) particles upregulate TNFα production by MLO-Y4 osteocytes in vitro, but the underlying mechanism has not been elucidated. Based on previous studies by others, we hypothesized that the calcineurin-nuclear factor of activated T cells (NFAT) pathway mediates CoCrMo particle-induced TNFα production in MLO-Y4 osteocytes. MLO-Y4 osteocytes exposed to CoCrMo particle treatment resulted in a rapid and significant increase in calcineurin activity. We also demonstrate that CoCrMo particle-induced upregulation of TNFα is reduced to control levels with calcineurin-NFAT inhibitors and this was also confirmed at mRNA level. Moreover, we demonstrate the localization of NFATs in MLO-Y4 osteocytes and that NFAT1 and 2 translocate to the nucleus upon CoCrMo particle treatment. Our results suggest that calcineurin-NFAT signaling is involved in TNFα production by MLO-Y4 osteocytes after CoCrMo particle treatment.
KW - calcineurin
KW - CoCrMo particles
KW - MLO-Y4 osteocytes
KW - nuclear factor of activated T cells (NFAT)
KW - tumor necrosis factor-α (TNFα)
UR - http://www.scopus.com/inward/record.url?scp=80054703582&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80054703582&partnerID=8YFLogxK
U2 - 10.1002/jor.21458
DO - 10.1002/jor.21458
M3 - Article
VL - 29
SP - 1867
EP - 1873
JO - Journal of Orthopaedic Research
JF - Journal of Orthopaedic Research
SN - 0736-0266
IS - 12
ER -