Effects of tamoxifen on tendon homeostasis and healing: Considerations for the use of tamoxifen‐inducible mouse models

Best, Katherine T.; Studentsova, Valentina; Ackerman, Jessica E.; Nichols, Anne E. C.; Myers, Marlin; Cobb, Justin; Knapp, Emma; Awad, Hani A.; Loiselle, Alayna E.

doi:10.1002/jor.24767

Cited by 7 publications

(5 citation statements)

References 38 publications

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“…Of note, Cre activity was reported in the tendons or paratenon of several Cre lines, including S100a4, (253) α-Sma, (25,26) Gdf5, (45,120,122) Sox9, (76,78) Prx1, (45) Pgr4, (25,120) Acan, (25) Gli1, (45) Col1, (130,133) Col2, (45,101,110,113) OC, (139) Ctsk, (32) and Wnt1-Cre (81) lines, and administration of tamoxifen in female, but not male, mice can significantly impair tendon homeostasis. (254) Tendons are surrounded by an elastic connective tissue known as the paratenon, marked by the expression of tubulin polymerization-promoting protein family member 3 (Tppp3). (255) The Tppp3P2A-iCreER T2-T2A-eGFP and Tppp3 P2A-ER T2 CreER T2 lines have been shown to express Cre recombinase in the paratenon with minimal expression in the tendon midsubstance, and can be used to target Tppp3-positive cell populations, which harbor tendon stem/progenitor cells.…”

Section: Cre Mice Targeting Tendons and Ligamentsmentioning

confidence: 99%

“…Of note, Cre activity was reported in the tendons or paratenon of several Cre lines, including S100a4 , ( 253 ) α‐Sma , ( 25,26 ) Gdf5 , ( 45,120,122 ) Sox9 , ( 76,78 ) Prx1 , ( 45 ) Pgr4 , ( 25,120 ) Acan , ( 25 ) Gli1 , ( 45 ) Col1 , ( 130,133 ) Col2 , ( 45,101,110,113 ) OC , ( 139 ) Ctsk , ( 32 ) and Wnt1‐Cre ( 81 ) lines, and administration of tamoxifen in female, but not male, mice can significantly impair tendon homeostasis. ( 254 )…”

Section: Cre Mice Targeting Tendons and Ligamentsmentioning

confidence: 99%

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Sites of Cre-recombinase activity in mouse lines targeting skeletal cells

Couasnay

Madel

Lim

et al. 2020

Journal of Bone and Mineral Research

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The Cre/Lox system is a powerful tool in the biologist's toolbox, allowing loss-of-function and gain-of-function studies, as well as lineage tracing, through gene recombination in a tissue-specific and inducible manner. Evidence indicates, however, that Cre transgenic lines have a far more nuanced and broader pattern of Cre activity than initially thought, exhibiting "off-target" activity in tissues/cells other than the ones they were originally designed to target. With the goal of facilitating the comparison and selection of optimal Cre lines to be used for the study of gene function, we have summarized in a single manuscript the major sites and timing of Cre activity of the main Cre lines available to target bone mesenchymal stem cells, chondrocytes, osteoblasts, osteocytes, tenocytes, and osteoclasts, along with their reported sites of "off-target" Cre activity. We also discuss characteristics, advantages, and limitations of these Cre lines for users to avoid common risks related to overinterpretation or misinterpretation based on the assumption of strict cell-type specificity or unaccounted effect of the Cre transgene or Cre inducers.

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Section: Cre Mice Targeting Tendons and Ligamentsmentioning

confidence: 99%

Section: Cre Mice Targeting Tendons and Ligamentsmentioning

confidence: 99%

Sites of Cre-recombinase activity in mouse lines targeting skeletal cells

Couasnay

Madel

Lim

et al. 2020

Journal of Bone and Mineral Research

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“…Tamoxifen (10–20 mg twice per day) has a longer history of use than rituximab as an additional drug to corticoids; it may be added to them or even offered as a single medication. This selective estrogen receptor modulator is beneficial not through its anti-estrogen capacity but via anti-fibrotic effects by stimulating transforming growth factor (TGF- β ), a cytokine released by fibroblasts and epithelial cells acting as a growth inhibitor of various cells (including fibroblasts) [ 12 , 13 ]. The need for anti-fibrotic effects also indicates mycophenolate mofetil (1 g twice per day) which is approved for systemic fibrosis, but it has limited applications due to severe side effects (pancytopenia or renal function damage) [ 2 , 6 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Reshaping the Concept of Riedel’s Thyroiditis into the Larger Frame of IgG4-Related Disease (Spectrum of IgG4-Related Thyroid Disease)

Cârșote

Nistor

2023

Biomedicines

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Recently, Riedel’s thyroiditis (RT) was assimilated into the larger spectrum of immunoglobulin IgG4-related disease (IgG4-RD) in addition to a particular frame of IgG4-related thyroid disease (IgG4-RTD), underlying IgG4-RT, IgG4-associated Hashimoto’s thyroiditis (and its fibrotic variant), and IgG4-related Graves’s disease. Our objective was to overview recent data on RT, particularly IgG4-RD and IgG4-RTD. The case and study– sample analysis (2019–2023) included 293 articles and selected 18 original studies: nine single case reports (N = 9, female/male = 2/1, aged: 34–79 years, 5/9 patients with serum IgG4 available data, 2/5 with high serum IgG4) and four case series (N = 21; 4/5 series provided data on IgG4 profile, 3/21 had serum IgG4 assays, and 2/3 had abnormally high values). IgG4-RD and thyroid findings were analyzed in three cohorts (N = 25). Another two studies (N = 11) specifically addressed IgG4-RTD components. On presentation, the patients may have hypothyroidism, transitory thyrotoxicosis, goiter, long-term history of positive anti-thyroid antibodies, and hypoechoic ultrasound thyroid pattern. The 5-year analysis (N = 66) showed the rate of serum IgG4 evaluation remained low; normal values do not exclude RT. Mandatory histological and immunohistochemistry reports point out a high content of IgG4-carrying plasma cells and IgG4/IgG ratio. Unless clinically evident, histological confirmation provides a prompt indication of starting corticoid therapy since this is the first-line option. Surgery, if feasible, is selective (non-responders to medical therapy, emergency tracheal intervention, and open/core needle biopsy). Current open issues are identifying the role of serum IgG4 assays in patients with IgG4-RD, finding out if all cases of RT are IgG4-mediated, applying IgG4-RTD criteria of differentiation among four entities, and providing an RT/IgG4-RTD guideline from diagnosis to therapy. It remains that the central aim of approaching RT in daily practice is the early index of suspicion in order to select patients referred for further procedures that provide enough histological/immunohistochemistry material to confirm RT and its high IgG4 burden.

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“…Various studies have also reported differential effects of tamoxifen treatment before animal injury models in males compared with females. 22–25 While the current study was not powered to evaluate sex differences in response to tamoxifen, this will be an important consideration for future analyses.…”

Section: Discussionmentioning

confidence: 99%

Confounding Effects of Tamoxifen: Cautionary and Practical Considerations for the Use of Tamoxifen-Inducible Mouse Models in Atherosclerosis Research—Brief Report

Dubner,

Lu,

Jolly

et al. 2023

ATVB

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Background: In recent years, fate-mapping lineage studies in mouse models have led to major advances in vascular biology by allowing investigators to track specific cell populations in vivo. One of the most frequently used lineage tracing approaches involves tamoxifen-inducible Cre ERT -LoxP systems. However, tamoxifen treatment can also promote effects independent of Cre recombinase activation, many of which have not been fully explored. Methods: To elucidate off-target effects of tamoxifen, male and female mice were either unmanipulated or injected with tamoxifen or corn oil. All mice received PCSK9-adeno-associated virus injections and a modified Western diet to induce hypercholesterolemia. After 2 weeks, serum cholesterol and liver morphology were assessed. To determine the duration of any tamoxifen effects in long-term atherosclerosis experiments, mice received either 12 days of tamoxifen at baseline or 12 days plus 2 sets of 5-day tamoxifen boosters; all mice received PCSK9-adeno-associated virus injections and a modified Western diet to induce hypercholesterolemia. After 24 weeks, serum cholesterol and aortic sinus plaque burden were measured. Results: After 2 weeks of atherogenic treatment, mice injected with tamoxifen demonstrated significantly reduced serum cholesterol levels compared with uninjected- or corn oil–treated mice. However, there were no differences in PCSK9-mediated knockdown of LDL (low-density lipoprotein) receptors between the groups. Additionally, tamoxifen-treated mice exhibited significantly increased hepatic lipid accumulation compared with the other groups. Finally, the effects of tamoxifen remained for at least 8 weeks after completion of injections, with mice demonstrating persistent decreased serum cholesterol and impaired atherosclerotic plaque formation. Conclusions: In this study, we establish that tamoxifen administration results in decreased serum cholesterol, decreased plaque formation, and increased hepatic lipid accumulation. These alterations represent significant confounding variables in atherosclerosis research, and we urge future investigators to take these findings into consideration when planning and executing their own atherosclerosis experiments.

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Effects of tamoxifen on tendon homeostasis and healing: Considerations for the use of tamoxifen‐inducible mouse models

Cited by 7 publications

References 38 publications

Sites of Cre-recombinase activity in mouse lines targeting skeletal cells

Sites of Cre-recombinase activity in mouse lines targeting skeletal cells

Reshaping the Concept of Riedel’s Thyroiditis into the Larger Frame of IgG4-Related Disease (Spectrum of IgG4-Related Thyroid Disease)

Confounding Effects of Tamoxifen: Cautionary and Practical Considerations for the Use of Tamoxifen-Inducible Mouse Models in Atherosclerosis Research—Brief Report

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