Progressive arthropathy in mice with a targeted disruption of theMop3/Bmal-1 locus

Bunger, Maureen K.; Walisser, Jacqueline A.; Sullivan, Ruth; Manley, Paul A.; Moran, Susan M.; Kalscheur, Vicki L.; Colman, Ricki J.; Bradfield, Christopher A.

doi:10.1002/gene.20102

Cited by 176 publications

(163 citation statements)

References 30 publications

(36 reference statements)

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“…Given the reduced BMAL1 levels we observed in both aged and diseased articular cartilage, it is reasonable to predict that disruption of chondrocyte Bmal1 expression and/or the circadian rhythm may compromise the daily maintenance and repair of cartilage tissue and become a significant contributing factor in joint diseases such as OA. It is interesting that our chondrocyte Bmal1-cKO mice showed profound and progressive lesions in the articular cartilage that were not found in global Bmal1-KO mice (22). The articular cartilage was reportedly normal in global Bmal1-KO Consistent with earlier reports on NFAT-mediated regulation of Sox9 (35,36), protein levels of SOX9 were concomitantly reduced in cKO knee cartilage ( Figure 6, B and C).…”

Section: Discussionsupporting

confidence: 90%

“…Similarly, tissue-specific disruption of the circadian clock in the liver led to hypoglycemia and increased glucose clearance (20), whereas conditional clock disruption in adipocytes caused obesity (21). Moreover, muscle-specific expression of BMAL1 in the global Bmal1-KO mouse model restored wheel-running activity levels and body weight (BW), but failed to rescue the calcific tendon/ligament phenotype (18,22). It remains unknown whether and how BMAL1 functions in chondrocytes to regulate cartilage tissue homeostasis in mice and humans.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity

Dudek¹,

Gossan²,

Yang³

et al. 2015

Journal of Clinical Investigation

158

202

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity

Dudek¹,

Gossan²,

Yang³

et al. 2015

Journal of Clinical Investigation

158

202

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“…The Bmal1 −/− mice die around 12 mo of age but, when they are 10 wk of age, Bmal1 −/− mice have similar body weight, normal skeletalmuscle fiber area, and normal distribution of circulating white blood cells compared with control mice (17). Our experiments were performed on mice 12-14 wk of age at a time when neither Bmal1 −/− nor Clock Δ19 mice show significant disease status (16,17,30). Thus, we suggest that the reduction in skeletal-muscle function is not likely a result of a specific behavior but instead due to alterations in molecular clock function.…”

Section: Discussionmentioning

confidence: 99%

CLOCK and BMAL1 regulate MyoD and are necessary for maintenance of skeletal muscle phenotype and function

Andrews

Zhang

McCarthy

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

302

341

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MyoD, a master regulator of myogenesis, exhibits a circadian rhythm in its mRNA and protein levels, suggesting a possible role in the daily maintenance of muscle phenotype and function. We report that MyoD is a direct target of the circadian transcriptional activators CLOCK and BMAL1, which bind in a rhythmic manner to the core enhancer of the MyoD promoter. Skeletal muscle of Clock Δ19 and Bmal1 −/− mutant mice exhibited ∼30% reductions in normalized maximal force. A similar reduction in force was observed at the single-fiber level. Electron microscopy (EM) showed that the myofilament architecture was disrupted in skeletal muscle of Clock Δ19 , Bmal1 −/− , and MyoD −/− mice. The alteration in myofilament organization was associated with decreased expression of actin, myosins, titin, and several MyoD target genes. EM analysis also demonstrated that muscle from both Clock Δ19 and Bmal1 −/− mice had a 40% reduction in mitochondrial volume. The remaining mitochondria in these mutant mice displayed aberrant morphology and increased uncoupling of respiration. This mitochondrial pathology was not seen in muscle of MyoD −/− mice. We suggest that altered expression of both Pgc-1α and Pgc-1β in Clock Δ19 and Bmal1 −/− mice may underlie this pathology. Taken together, our results demonstrate that disruption of CLOCK or BMAL1 leads to structural and functional alterations at the cellular level in skeletal muscle. The identification of MyoD as a clock-controlled gene provides a mechanism by which the circadian clock may generate a muscle-specific circadian transcriptome in an adaptive role for the daily maintenance of adult skeletal muscle.circadian clock | myofilaments | mitochondria A fundamental, evolutionarily conserved property of most organisms, from cyanobacteria to plants and animals, is the daily cycling of their internal physiology as well as certain behaviors in animals, such as sleep and feeding (1). The timing of these circadian rhythms is synchronized to the environment by external cues, with light and nutrient availability being two of the most salient entrainment cues (2). The synchronization of endogenous circadian rhythms with the daily cycles in the environment provides an adaptive mechanism for organisms to anticipate cyclic demands on cellular physiology and behavior (3, 4). At the molecular level, the circadian clock represents a well-defined gene regulatory network composed of transcriptional-translational feedback loops (5). The positive arm of the loop is composed of the transcription factors CLOCK and BMAL1, which heterodimerize and bind to E-box elements on target genes such as Per1 to drive the negative part of the feedback loop (5). More recently, the same molecular clock factors that have been identified in the central clock in the suprachiasmatic nucleus have been found to exist in most peripheral tissues (reviewed in ref. 6).We recently characterized the circadian transcriptome of adult skeletal muscle. These mRNAs exhibit significant oscillation in gene expression with a repeating period len...

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“…Increasing evidence has implicated the circadian system in the regulation of such processes as glucose homeostasis, obesity, bone formation, stress response, and others (Fu et al 2002(Fu et al , 2005Miller et al 2004;Bunger et al 2005;Gorbacheva et al 2005;Spanagel et al 2005;Turek et al 2005). These findings dictate reconsideration of the role of core clock proteins and the circadian system in prevention, development, and/or progression of various pathologies.…”

Section: Early Aging Caused By Bmal1 Deficiencymentioning

confidence: 99%

“…Hence, some circadian proteins play important roles in organ physiology that are not necessarily linked to their circadian function. This is certainly true for BMAL1, since Bmal1 −/− mice, in addition to loss of circadian rhythms, display a number of phenotypes including infertility (Kennaway 2005), defective glucose homeostasis (Rudic et al 2004), idiopathic calcification and ossification of hind limb joints (Bunger et al 2005), and increased sensitivity to chemotherapy and radiation (Gorbacheva et al 2005). To further investigate the role of BMAL1 in normal physiology, we monitored a large group of Bmal1 −/− knockout (KO) and wild-type mice for their entire lifespan.…”

mentioning

confidence: 99%

Early aging and age-related pathologies in mice deficient in BMAL1, the core componentof the circadian clock

Kondratov¹,

Kondratova²,

Gorbacheva³

et al. 2006

Genes Dev.

982

884

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Mice deficient in the circadian transcription factor BMAL1 (brain and muscle ARNT-like protein) have impaired circadian behavior and demonstrate loss of rhythmicity in the expression of target genes. Here we report that Bmal1 −/− mice have reduced lifespans and display various symptoms of premature aging including sarcopenia, cataracts, less subcutaneous fat, organ shrinkage, and others. The early aging phenotype correlates with increased levels of reactive oxygen species in some tissues of the Bmal1 −/− animals. These findings, together with data on CLOCK/BMAL1-dependent control of stress responses, may provide a mechanistic explanation for the early onset of age-related pathologies in the absence of BMAL1.Supplemental material is available at http://www.genesdev.org.Received March 22, 2006; revised version accepted May 9, 2006. BMAL1 (brain and muscle ARNT-like protein, also known as MOP3 or ARNT3) belongs to the family of the basic helix-loop-helix (bHLH)-PAS domain-containing transcription factors. In a complex with another member of this family, CLOCK, BMAL1 regulates expression of genes through E-box elements in their promoters. BMAL1, CLOCK, and some of their transcriptional targets (PERIODs and CRYPTOCHROMEs) are the key components of the molecular oscillator that generates circadian rhythms. These 24-h oscillations in behavior, physiology, and metabolism are thought to ensure adaptation of organisms to the 24-h periodicity of the Earth's rotation (Panda et al. 2002b;Lowrey and Takahashi 2004). Although the master circadian clock is located within the hypothalamic suprachiasmatic nucleus (SCN), the key circadian proteins are expressed in many peripheral tissues, determining circadian periodicity in gene expression and physiology for many organs (Reppert and Weaver 2002). Indeed, microarray data show that up to 10% of genes in different tissues are directly or indirectly regulated by the circadian clock system (Panda et al. 2002a;Storch et al. 2002). At the same time, only a few oscillating genes (most of them encoding components of the molecular clock itself) are common to all organs tested. Since different tissues have characteristic sets of genes with clock-regulated timing and amplitude of expression (Panda et al. 2002a;Storch et al. 2002), it is likely that the circadian clock is involved in control of homeostasis in different organs.Mice with mutations or targeted disruptions of core circadian genes that have been generated during the last decade all show impaired circadian behavior and deregulation of circadian patterns in gene expression (Lowrey and Takahashi 2004). In addition to this universal phenotype, other pathological defects are specific for particular circadian mutants. Thus, Clock mutation results in reduced fertility and complications of pregnancy (Miller et al. 2004), obesity and metabolic syndrome (Turek et al. 2005), and sensitization to cocaine (McClung et al. 2005). Period2 deficiency leads to the enhanced voluntary alcohol consumption and alterations in the glutamatergic syste...

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Progressive arthropathy in mice with a targeted disruption of theMop3/Bmal-1 locus

Cited by 176 publications

References 30 publications

The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity

The chondrocyte clock gene Bmal1 controls cartilage homeostasis and integrity

CLOCK and BMAL1 regulate MyoD and are necessary for maintenance of skeletal muscle phenotype and function

Early aging and age-related pathologies in mice deficient in BMAL1, the core componentof the circadian clock

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