Tamoxifen-inducible Cre-recombination in articular chondrocytes of adult Col2a1-CreERT2 transgenic mice

Zhu, Min; Chen, M.; Lichtler, Alex; O’Keefe, Regis J.; Chen, D.

doi:10.1016/j.joca.2007.08.001

Cited by 47 publications

(53 citation statements)

References 9 publications

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“…The Col2a1Cre and AcanCreER drivers also cause FOXO deletion in other cartilaginous structures such as in the articular cartilage of the synovial joints and the growth plates (Henry et al, 2009; Zhu, Chen, Lichtler, O'Keefe, & Chen, 2008). We have recently reported the knee articular cartilage phenotype in these mouse models and demonstrated that FOXO are critical mediators of chondrocyte homeostasis by regulating PRG4 expression and maintaining the integrity of the cartilage superficial zone (Matsuzaki et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

FOXO are required for intervertebral disk homeostasis during aging and their deficiency promotes disk degeneration

et al. 2018

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Intervertebral disk (IVD) degeneration is a prevalent age‐associated musculoskeletal disorder and a major cause of chronic low back pain. Aging is the main risk factor for the disease, but the molecular mechanisms regulating IVD homeostasis during aging are unknown. The aim of this study was to investigate the function of FOXO, a family of transcription factors linked to aging and longevity, in IVD aging and age‐related degeneration. Conditional deletion of all FOXO isoforms (FOXO1, 3, and 4) in IVD using the Col2a1Cre and AcanCreER mouse resulted in spontaneous development of IVD degeneration that was driven by severe cell loss in the nucleus pulposus (NP) and cartilaginous endplates (EP). Conditional deletion of individual FOXO in mature mice showed that FOXO1 and FOXO3 are the dominant isoforms and have redundant functions in promoting IVD homeostasis. Gene expression analyses indicated impaired autophagy and reduced antioxidant defenses in the NP of FOXO‐deficient IVD. In primary human NP cells, FOXO directly regulated autophagy and adaptation to hypoxia and promoted resistance to oxidative and inflammatory stress. Our findings demonstrate that FOXO are critical regulators of IVD homeostasis during aging and suggest that maintaining or restoring FOXO expression can be a therapeutic strategy to promote healthy IVD aging and delay the onset of IVD degeneration.

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Section: Discussionmentioning

confidence: 99%

FOXO are required for intervertebral disk homeostasis during aging and their deficiency promotes disk degeneration

et al. 2018

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“…Col2a1-CreERT2 transgenic mice were generated as described previously [21,22]. GR flox/flox transgenic mice were backcrossed to the C57BL/6 background for 10 generations as previously described [23,24].…”

Section: Methodsmentioning

confidence: 99%

“…The aim of this study was therefore to investigate the role of endogenous GCs in cartilage and bone developments in normal physiology, and during fracture healing. To address this aim, we generated tamoxifen-inducible cartilage-specific GR knockout mice (Col2a1-CreERT2; GR flox/flox ), which allow precise temporal control of GR deletion within chondrocytes [20,21]. …”

Section: Introductionmentioning

confidence: 99%

Disruption of glucocorticoid signaling in chondrocytes delays metaphyseal fracture healing but does not affect normal cartilage and bone development

Henneicke

Zhang

et al. 2014

Bone

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States of glucocorticoid excess are associated with defects in chondrocyte function. Most prominently there is a reduction in linear growth but delayed healing of fractures that require endochondral ossification to also occur. In contrast, little is known about the role of endogenous glucocorticoids in chondrocyte function. As glucocorticoids exert their cellular actions through the glucocorticoid receptor (GR), we aimed to elucidate the role of endogenous glucocorticoids in chondrocyte function in vivo through characterization of tamoxifen-inducible chondrocyte-specific GR knockout (chGRKO) mice in which the GR was deleted at various post-natal ages. Knee joint architecture, cartilage structure, growth plates, intervertebral discs, long bone length and bone micro-architecture were similar in chGRKO and control mice at all ages. Analysis of fracture healing in chGRKO and control mice demonstrated that in metaphyseal fractures, chGRKO mice formed a larger cartilaginous callus at 1 and 2 week post-surgery, as well as a smaller amount of well-mineralized bony callus at the fracture site 4 week post-surgery, when compared to control mice. In contrast, chondrocyte-specific GR knockout did not affect diaphyseal fracture healing. We conclude that endogenous GC signaling in chondrocytes plays an important role during metaphyseal fracture healing but is not essential for normal long bone growth.

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“…Consistent with these findings, Smad3 knockout mice show progressive articular cartilage degradation resembling human OA [44]. In order to overcome embryonic lethality and redundancy, we generated chondrocyte-specific Tgfbr2 conditional knockout mice (Tgfbr2 cKO or Tgfbr2Col2CreER mice) in which deletion of the Tgfbr2 gene is mediated by Cre recombinase driven by the chondrocyte-specific Col2a1 promoter in a tamoxifen (TM)-inducible manner [45, 46]. These mice exhibit typical clinical features of OA, including cell cloning, chondrocyte hypertrophy, cartilage surface fibrillation, vertical clefts, and severe articular cartilage damage as well as the formation of chondrophytes and osteophytes [47].…”

Section: Molecular Mechanisms Related To Oa Pathogenesismentioning

confidence: 99%

Osteoarthritis Pathogenesis: A Review of Molecular Mechanisms

et al. 2014

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Osteoarthritis (OA), the most prevalent chronic joint disease, increases in prevalence with age, and affects majority of individuals over the age of 65 and is a leading musculoskeletal cause of impaired mobility in the elderly. Because the precise molecular mechanisms which are involved in the degradation of cartilage matrix and development of OA are poorly understood and there are currently no effective interventions to decelerate the progression of OA or retard the irreversible degradation of cartilage except for total joint replacement surgery. In this paper, the important molecular mechanisms related to OA pathogenesis will be summarized and new insights into potential molecular targets for the prevention and treatment of OA will be provided.

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Tamoxifen-inducible Cre-recombination in articular chondrocytes of adult Col2a1-CreERT2 transgenic mice

Abstract: Our findings demonstrate that the Col2a1-CreER(T2) transgenic mouse model is a valuable tool to target genes specifically expressed in articular chondrocytes in a temporally controlled manner in adult mice.

Cited by 47 publications

References 9 publications

FOXO are required for intervertebral disk homeostasis during aging and their deficiency promotes disk degeneration

FOXO are required for intervertebral disk homeostasis during aging and their deficiency promotes disk degeneration

Disruption of glucocorticoid signaling in chondrocytes delays metaphyseal fracture healing but does not affect normal cartilage and bone development

Osteoarthritis Pathogenesis: A Review of Molecular Mechanisms

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