Fracture healing and lipid mediators

O’Connor, J. P.; Manigrasso, Michaele B.; Kim, Brian D.; Subramanian, Sangeeta

doi:10.1038/bonekey.2014.12

Cited by 31 publications

(25 citation statements)

References 53 publications

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“…Other genes known to be upregulated after osteoclastogenesis included tank (Maruyama et al, 2012) (FC=+1.51 after LE135 treatment), and lipid mediators including Alox5 (cluster 5), Alox15b and Aloxe3. In mammals, loss of lipid mediators Alox5 and Alox15b leads to an increase in bone, and increase of the activity of these lipid mediators decreases bone density (O'Connor et al, 2014). Other gene expression patterns were suggestive for an effect on skeletal progenitor differentiation including a FC of +2.2 of Tgfβ2 in LE135-treated limbs (FC=+1.73 in RA treated), a FC of +1.47 of Tgfβ1 in LE135-treated limbs (FC=+3.30 in RA treated), and a significant downregulation of Bmpr1b (FC=−2.57 in LE135 and FC=−1.77 in RA-treated limbs).…”

Section: Gene Transcriptional Responses Associated With Limb Truncationsmentioning

confidence: 99%

Retinoic acid receptor regulation of epimorphic and homeostatic regeneration in the axolotl

et al. 2017

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Salamanders are capable of regenerating amputated limbs by generating a mass of lineage-restricted cells called a blastema. Blastemas only generate structures distal to their origin unless treated with retinoic acid (RA), which results in proximodistal (PD) limb duplications. Little is known about the transcriptional network that regulates PD duplication. In this study, we target specific retinoic acid receptors (RARs) to either PD duplicate (RA treatment or RARγ agonist) or truncate (RARβ antagonist) regenerating limbs. RARE-EGFP reporter axolotls showed divergent reporter activity in limbs undergoing PD duplication versus truncation, suggesting differences in patterning and skeletal regeneration. Transcriptomics identified expression patterns that explain PD duplication, including upregulation of proximal homeobox gene expression and silencing of distal-associated genes, whereas limb truncation was associated with disrupted skeletal differentiation. RARβ antagonism in uninjured limbs induced a loss of skeletal integrity leading to long bone regression and loss of skeletal turnover. Overall, mechanisms were identified that regulate the multifaceted roles of RARs in the salamander limb including regulation of skeletal patterning during epimorphic regeneration, skeletal tissue differentiation during regeneration, and homeostatic regeneration of intact limbs.

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Section: Gene Transcriptional Responses Associated With Limb Truncationsmentioning

confidence: 99%

Retinoic acid receptor regulation of epimorphic and homeostatic regeneration in the axolotl

et al. 2017

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“…Cyclooxygenase‐2 (COX‐2) and 5‐lipoxygenase (5‐LO) catalyze synthesis of lipid mediators that regulate inflammation and bone fracture healing. Pharmacological inhibition or genetic ablation of COX‐2 impairs fracture healing, while inhibition or ablation of 5‐LO accelerates healing . COX‐2 and 5‐LO catalyze the synthesis of prostaglandins and leukotrienes, respectively, which are lipid mediators that regulate inflammation and other processes, including tissue regeneration .…”

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confidence: 99%

Variation in lipid mediator and cytokine levels during mouse femur fracture healing

Hao

Cottrell

O’Connor

2016

Journal Orthopaedic Research

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Fracture healing is regulated by a variety of inflammatory mediators and growth factors which act over time to regenerate the injured tissue. This study used a mouse femur fracture model to quantify the temporal expression pattern of lipid mediators, cytokines, and related mRNAs during healing. Cyclooxygenase (COX-1 and COX-2) and 5-lipoxygenase (5-LO) derived lipid mediators, cytokines, and mRNA levels were quantified using mass spectrometry (LC-MS/MS), bead-based multiplex assays (xMAP), and quantitative PCR of cDNA (RTqPCR), respectively. Our analysis found that, the early inflammatory response (between 0 and 4 days after fracture) in the mouse femur fracture model coincided with elevated levels of COX-derived lipid mediators and inflammatory cytokines but with decreased levels of 5-LO-derived lipid mediators. Further, the COX-derived lipid mediators remained elevated for at least 7 days after fracture, suggesting that the COX-derived lipid mediators have additional functions during later phases of the fracture healing response. Differences were also found between mRNA levels and corresponding cytokines and lipid mediator levels, supporting a role for post-transcriptional regulation of gene expression. The temporal changes in fracture callus lipid mediator levels and inflammatory cytokines support a general positive role for inflammatory cytokines and COX-derived lipid mediators on fracture healing and a general negative role for 5-lipoxygenase derived lipid mediators during the initial stages of repair. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1883-1893, 2016.

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“…The COX enzyme, the key target of NSAID, plays a vital role in the generation of the inflammatory response during the bone healing process by converting arachidonic acid to prostaglandins 9 . Also, the COX enzyme and PGE2 have been found to affect the response of immune cells such as macrophages during bone healing in the synthesis and release of pro-iflammatory and anti-inflammtory mediators 15,59,60 .…”

Section: Discussionmentioning

confidence: 99%

“…Inflammation is essential in healing 9 . For example, when connective tissues are injured, an inflammatory response starts by the conversion of arachidonic acid (AA), either into prostaglandin H2 (PGH2) via cyclooxygenase (COX), or into interleukotrien A4 (LTA4) via 5-lipoxygenase .…”

mentioning

confidence: 99%

“…For example, when connective tissues are injured, an inflammatory response starts by the conversion of arachidonic acid (AA), either into prostaglandin H2 (PGH2) via cyclooxygenase (COX), or into interleukotrien A4 (LTA4) via 5-lipoxygenase . Downstream specific synthetase enzymes convert PGH2 and LTA4 into bioactive lipid mediators, such as prostaglandin E2 (PGE2), which play a crucial role in tissue repair 9,10 . Also, release of pro-inflammatory cytokines and growth factors at the injury site, results in increased secretion of prostaglandins.…”

mentioning

confidence: 99%

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Chronotherapy of Non-Steroidal Anti-Inflammatory Drugs May Enhance Postoperative Recovery

Al-Waeli

Nicolau

Stone

et al. 2020

Sci Rep

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Postoperative pain relief is crucial for full recovery. With the ongoing opioid epidemic and the insufficient effect of acetaminophen on severe pain; non-steroidal anti-inflammatory drugs (NSAIDs) are heavily used to alleviate this pain. However, NSAIDs are known to inhibit postoperative healing of connective tissues by inhibiting prostaglandin signaling. Pain intensity, inflammatory mediators associated with wound healing and the pharmacological action of NSAIDs vary throughout the day due to the circadian rhythm regulated by the clock genes. According to this rhythm, most of wound healing mediators and connective tissue formation occurs during the resting phase, while pain, inflammation and tissue resorption occur during the active period of the day. Here we show, in a murine tibia fracture surgical model, that NSAIDs are most effective in managing postoperative pain, healing and recovery when drug administration is limited to the active phase of the circadian rhythm. Limiting NSAID treatment to the active phase of the circadian rhythm resulted in overexpression of circadian clock genes, such as Period 2 (Per2) at the healing callus, and increased serum levels of anti-inflammatory cytokines interleukin-13 (IL-13), interleukin-4 (IL-4) and vascular endothelial growth factor. By contrast, NSAID administration during the resting phase resulted in severe bone healing impairment. open Scientific RepoRtS | (2020) 10:468 | https://doi.org/10.1038/s41598-019-57215-y www.nature.com/scientificreports www.nature.com/scientificreports/ and Table S2). For instance, macrophage activity, leukocyte recruitment, and pro-inflammatory mediators such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-12 (IL-12) increase at the beginning of daily activity. During this phase, the levels of Tol-Like Receptors TLR9 and TLR4 also increase, leading to the upregulation of CCL2, CXCL1, CCL5, and subsequent leukocyte recruitment and potential tissue damage in injured sites 12-15 ( Fig. 1). By contrast, anti-inflammatory mediators and other growth or angiogenesis factors, such as the vascular endothelial growth factor (VEGF), peak during the resting phase 13,16,17 ( Fig. 1 and Table S2).The circadian rhythm affects many aspects of connective tissue metabolism 18 . A 24-hour oscillation occurs in bone tissue during growth 19 , formation, resorption 20,21 , and in the endochondral ossification during bone fracture healing 21 . Bone formation occurs during the resting period, and resorption occurs mostly during the active period 21 . Experimental studies in rodents and humans reveal that the disruption of sleep and circadian rhythm impairs bone formation 22 . All bone cells such as osteoblasts, osteoclasts, and chondrocytes express clock genes, such as Per or Cry, that influence bone volume regulation 23,24 . Cry2 influences the osteoclastic activity and Per2 regulates osteoblast activity 25 . The circadian clock also affects pain, with sensitivity peaking during the active phase 26 . Part of the pain response oscillation could b...

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Fracture healing and lipid mediators

Cited by 31 publications

References 53 publications

Retinoic acid receptor regulation of epimorphic and homeostatic regeneration in the axolotl

Retinoic acid receptor regulation of epimorphic and homeostatic regeneration in the axolotl

Variation in lipid mediator and cytokine levels during mouse femur fracture healing

Chronotherapy of Non-Steroidal Anti-Inflammatory Drugs May Enhance Postoperative Recovery

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