Inducible cyclo-oxygenase (COX-2) mediates the induction of bone formation by mechanical loading in vivo

Forwood, Mark R.

doi:10.1002/jbmr.5650111112

Cited by 328 publications

(170 citation statements)

References 39 publications

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“…Possible signal molecules, which involved in the promoting effects of LIPUS in the present study, might be the followings: Prostaglandin E2, nitric oxide, vascular endothelial growth factors (VEGF) because enhancement of the production of these signal molecules by mechanical stress has been reported [22][23][24]. Although the precise mechanism of the present enhancement of bone regeneration is not clear, it is likely that LIPUS stimulated cellular migration, proliferation and differentiation which were controlled by these signal molecules [25,26].…”

Section: Figurementioning

confidence: 65%

Effects of low intensity pulsed ultrasound stimulation on bone regeneration in rat parietal bone defect model

Chen¹,

Jia²,

Noritake³

et al. 2013

OJRM

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Purpose: Low intensity pulsed ultrasound stimulation (LIPUS) has been clinically applied to promote bone fracture healing in the orthopedic field. Thus, it is likely that LIPUS also stimulates bone regeneration in bone defects in the cranial-maxillofacial area. However, this has not been clearly proved. Furthermore, optimal time point and period of the application after the surgery has not been reported. The purpose of the present study was to evaluate the effect of LIPUS on bone regeneration in the rat parietal bone defects especially focusing on time and period of the application. Materials and Methods: Eighteen Wistar rats (14 weeks old) were divided into 6 groups: 5 experimental groups and a control group. Bone defect of 5 mm diameter was prepared on each side of the parietal bone and customized gelatin membranes were placed over the bone defects. LIPUS (160 mW/cm 2 , 15 min/day) was applied to the defect area with an active transducer externally in the experimental groups according to the schedules of the applications: Group 1 (day 6 -12), group 2 (day 13 -19), group 3 (day 20 -26), group 4 (day 6 -19) and group 5 (day 6 -26). All the animals were sacrificed at 28 days. The defects were analyzed with micro CT and then histologically. Results: In Group 1, new bone formation was significantly promoted and the newly-formed bone was thick and matured compared to the one of the control group. In other experimental groups there were tendencies of stimulation of new bone formation; however, they were not statistically significant. Discussion and Conclusion: The present study demonstrated that amount of new bone formation in the bone defect depended on the time and period of LIPUS application. It has been suggested that application of LIPUS at an early healing period, the second week after the surgery, effectively accelerated new bone formation.

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Section: Figurementioning

confidence: 65%

Effects of low intensity pulsed ultrasound stimulation on bone regeneration in rat parietal bone defect model

Chen¹,

Jia²,

Noritake³

et al. 2013

OJRM

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“…34,43,44 Both non-selective and selective COX-2 inhibitors also reduce mechanically induced lamellar bone formation when given prior to mechanical loading. 3 In these experiments, selective COX-2 inhibitors demonstrate a greater effect. 3,45 Significant decreases in lamellar bone area with ibuprofen treatment were not seen until 6 weeks after loading.…”

Section: Discussionmentioning

confidence: 83%

“…3 In these experiments, selective COX-2 inhibitors demonstrate a greater effect. 3,45 Significant decreases in lamellar bone area with ibuprofen treatment were not seen until 6 weeks after loading. The timing of this effect may be a function of the time required to achieve an area of new bone formation great enough to detect significant changes.…”

Section: Discussionmentioning

confidence: 83%

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Selective and non‐selective cyclooxygenase inhibitors delay stress fracture healing in the rat ulna

Kidd

Cowling

et al. 2012

Journal Orthopaedic Research

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Anti-inflammatory drugs are widely used to manage pain associated with stress fractures (SFxs), but little is known about their effects on healing of those injuries. We hypothesized that selective and non-selective anti-inflammatory treatments would retard the healing of SFx in the rat ulna. SFxs were created by cyclic loading of the ulna in Wistar rats. Ulnae were harvested 2, 4 or 6 weeks following loading. Rats were treated with non-selective NSAID, ibuprofen (30 mg/kg/day); selective COX-2 inhibition, [5,5-dimethyl-3-3 (3 fluorophenyl)-4-(4 methylsulfonal) phenyl-2 (5H)-furanone] (DFU) (2.0 mg/kg/day); or the novel c5a anatagonist PMX53 (10 mg/kg/ day, 4 and 6 weeks only); with appropriate vehicle as control. Quantitative histomorphometric measurements of SFx healing were undertaken. Treatment with the selective COX-2 inhibitor, DFU, reduced the area of resorption along the fracture line at 2 weeks, without affecting bone formation at later stages. Treatment with the non-selective, NSAID, ibuprofen decreased both bone resorption and bone formation so that there was significantly reduced length and area of remodeling and lamellar bone formation within the remodeling unit at 6 weeks after fracture. The C5a receptor antagonist PMX53 had no effect on SFx healing at 4 or 6 weeks after loading, suggesting that PMX53 would not delay SFx healing. Both selective COX-2 inhibitors and non-selective NSAIDs have the potential to compromise SFx healing, and should be used with caution when SFx is diagnosed or suspected. ß

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“…12,17 COX-2 and PGE2 are known mediators of the bone-forming response to external stimulation. 18 However, there are no reports concerning the mechanism by which LIPUS accelerates COX-2 expression in Mj. In the presence of nTNF, the COX-2-enhancing effect of LIPUS was weakened (Fig.…”

Section: Discussionmentioning

confidence: 99%

Role of the tumor necrosis factor‐α, cyclooxygenase‐2, prostaglandin E2, and effect of low‐intensity pulsed ultrasound in an in vitro herniated disc resorption model

Iwabuchi¹,

Ito²,

Chikanishi³

et al. 2008

Journal Orthopaedic Research

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Spontaneous herniated disc resorption occurs via inflammatory reactions involving abundant neovascularization and macrophage phagocytotic activity. Nonthermal low-intensity pulsed ultrasound (LIPUS) treatment might be effective in shortening the duration of disc resorption. We developed a rat in vitro resorption model in which a coccygeal intervertebral disc and peritoneal macrophages were cocultured. Secretion of tumor necrosis factor-a (TNF-a) from macrophages was promoted by LIPUS, and the process of disc degeneration was thus accelerated. In this study, we further examined the effects of LIPUS using this in vitro model focusing on whether LIPUS affects cyclooxygenase-2 (COX-2) signaling pathways. We found that the levels of COX-2 and prostaglandin E2 (PGE2) secreted from macrophages were increased by LIPUS. However, these phenomena were not caused by LIPUS directly, as the levels of these substances were reduced by neutralizing TNF-a activity. Moreover, the wet weights of the disc samples were not changed by addition of PGE2, but were reduced by recombinant TNF-a. Our results suggest that the effects of LIPUS in enhancing the process of herniated disc resorption are caused mainly by TNF-a. Keywords: low-intensity pulsed ultrasound; herniated disc; TNF-a; COX-2; PGE2A herniated disc (HD) is defined as a degenerated intervertebral disc protruding toward the spinal canal. Mechanical compression by an HD and chemical stimulation with substances such as tumor necrosis factor-a (TNF-a) can be potential causes of radiculopathy. 1 Pain may be relieved by surgical removal of the ruptured disc. Recently, spontaneous resorption of exposed HDs was recognized by magnetic resonance imaging (MRI), 2 and conservative treatments are now often selected to relieve pain. 3 The mechanism of HD resorption may involve inflammatory reactions correlated with abundant neovascularization and macrophage (Mj) phagocytotic activity. 4,5 TNF-a stimulates matrix metalloproteinase (MMP)-3 in the disc in an autocrine/paracrine manner, causing further infiltration of Mj and degeneration of extracellular matrix. [4][5][6] However, the resorption mechanism has not been clarified.We previously revealed that nonthermal low-intensity pulsed ultrasound (LIPUS) stimulation was effective for enhancing resorption, and accelerating the rate of disc degeneration. 7 LIPUS therapy promotes bone fracture healing in human subjects, 8 modulates gene expression in osteoblasts or chondrocytes, 9,10 and influences second messenger activities related to angiogenesis. We hypothesized that LIPUS stimulation would promote inflammatory activity, and therefore we examined the effects of LIPUS on a rat HD resorption model involving coculture of coccygeal ID tissues and peritoneal Mj. The LIPUS exposure enhanced TNF-a secretion by Mj, and disc wet weights were decreased by stimulation after 4 days of culture. 7 These results suggested that LIPUS activates the infiltration of Mj into cocultured disc samples, thus accelerating resorption.Cyclooxygenase-2 (COX-2...

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Inducible cyclo-oxygenase (COX-2) mediates the induction of bone formation by mechanical loading in vivo

Cited by 328 publications

References 39 publications

Effects of low intensity pulsed ultrasound stimulation on bone regeneration in rat parietal bone defect model

Effects of low intensity pulsed ultrasound stimulation on bone regeneration in rat parietal bone defect model

Selective and non‐selective cyclooxygenase inhibitors delay stress fracture healing in the rat ulna

Role of the tumor necrosis factor‐α, cyclooxygenase‐2, prostaglandin E2, and effect of low‐intensity pulsed ultrasound in an in vitro herniated disc resorption model

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