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  • Farr, Joshua N  (4)
  • Thicke, Brianne S  (4)
  • 1
    Online Resource
    Online Resource
    miR‐219a‐5p Regulates Rorβ During Osteoblast Differentiation and in Age‐related Bone Loss
    Wiley ; 2019
    In:  Journal of Bone and Mineral Research Vol. 34, No. 1 ( 2019-01), p. 135-144
    Details
    In: Journal of Bone and Mineral Research, Wiley, Vol. 34, No. 1 ( 2019-01), p. 135-144
    Abstract: Developing novel approaches to treat skeletal disorders requires an understanding of how critical molecular factors regulate osteoblast differentiation and bone remodeling. We have reported that (1) retinoic acid receptor‐related orphan receptor beta (Rorβ) is upregulated in bone samples isolated from aged mice and humans in vivo; (2) Rorβ expression is inhibited during osteoblastic differentiation in vitro; and (3) genetic deletion of Rorβ in mice results in preservation of bone mass during aging. These data establish that Rorβ inhibits osteogenesis and that strict control of Rorβ expression is essential for bone homeostasis. Because microRNAs (miRNAs) are known to play important roles in the regulation of gene expression in bone, we explored whether a predicted subset of nine miRNAs regulates Rorβ expression during both osteoblast differentiation and aging. Mouse osteoblastic cells were differentiated in vitro and assayed for Rorβ and miRNA expression. As Rorβ levels declined with differentiation, the expression of many of these miRNAs, including miR‐219a‐5p , was increased. We further demonstrated that miR‐219a‐5p was decreased in bone samples from old (24‐month) mice, as compared with young (6‐month) mice, concomitant with increased Rorβ expression. Importantly, we also found that miR‐219a‐5p expression was decreased in aged human bone biopsies compared with young controls, demonstrating that this phenomenon also occurs in aging bone in humans. Inhibition of miR‐219a‐5p in mouse calvarial osteoblasts led to increased Rorβ expression and decreased alkaline phosphatase expression and activity, whereas a miR‐219a‐5p mimic decreased Rorβ expression and increased osteogenic activity. Finally, we demonstrated that miR‐219a‐5p physically interacts with Rorβ mRNA in osteoblasts, defining Rorβ as a true molecular target of miR‐219a‐5p . Overall, our findings demonstrate that miR‐219a‐5p is involved in the regulation of Rorβ in both mouse and human bone. © 2018 American Society for Bone and Mineral Research.
    Type of Medium: Online Resource
    ISSN: 0884-0431 , 1523-4681
    URL: Issue
    URL: Article
    DOI: 10.1002/jbmr.v34.1
    DOI: 10.1002/jbmr.3586
    RVK:
    XA 52230
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2008867-X
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  • 2
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    Independent Roles of Estrogen Deficiency and Cellular Senescence in the Pathogenesis of Osteoporosis: Evidence in Young Adult Mice and Older Humans
    Wiley ; 2019
    In:  Journal of Bone and Mineral Research Vol. 34, No. 8 ( 2019-08), p. 1407-1418
    Details
    In: Journal of Bone and Mineral Research, Wiley, Vol. 34, No. 8 ( 2019-08), p. 1407-1418
    Abstract: Estrogen deficiency is a seminal mechanism in the pathogenesis of osteoporosis. Mounting evidence, however, establishes that cellular senescence, a fundamental mechanism that drives multiple age‐related diseases, also causes osteoporosis. Recently, we systematically identified an accumulation of senescent cells, characterized by increased p16 Ink4a and p21 Cip1 levels and development of a senescence‐associated secretory phenotype (SASP), in mouse bone/marrow and human bone with aging. We then demonstrated that elimination of senescent cells prevented age‐related bone loss using multiple approaches, eg, treating old mice expressing a “suicide” transgene, INK‐ATTAC , with AP20187 to induce apoptosis of p16 Ink4a ‐senescent cells or periodically treating old wild‐type mice with “senolytics,” ie, drugs that eliminate senescent cells. Here, we investigate a possible role for estrogen in the regulation of cellular senescence using multiple approaches. First, sex steroid deficiency 2 months after ovariectomy (OVX, n  = 15) or orchidectomy (ORCH, n  = 15) versus sham surgery (SHAM, n  = 15/sex) in young adult (4‐month‐old) wild‐type mice did not alter senescence biomarkers or induce a SASP in bone. Next, in elderly postmenopausal women, 3 weeks of estrogen therapy ( n  = 10; 74 ± 5 years) compared with no treatment ( n  = 10; 78 ± 5 years) did not alter senescence biomarkers or the SASP in human bone biopsies. Finally, young adult (4‐month‐old) female INK‐ATTAC mice were randomized ( n  = 17/group) to SHAM+Vehicle, OVX+Vehicle, or OVX+AP20187 for 2 months. As anticipated, OVX+Vehicle caused significant trabecular/cortical bone loss compared with SHAM+Vehicle. However, treatment with AP20187, which eliminates senescent cells in INK‐ATTAC mice, did not rescue the OVX‐induced bone loss or alter senescence biomarkers. Collectively, our data establish independent roles of estrogen deficiency and cellular senescence in the pathogenesis of osteoporosis, which has important implications for testing novel senolytics for skeletal efficacy, as these drugs will need to be evaluated in preclinical models of aging as opposed to the current FDA model of prevention of OVX‐induced bone loss. © 2019 American Society for Bone and Mineral Research.
    Type of Medium: Online Resource
    ISSN: 0884-0431 , 1523-4681
    URL: Issue
    URL: Article
    DOI: 10.1002/jbmr.v34.8
    DOI: 10.1002/jbmr.3729
    RVK:
    XA 52230
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2008867-X
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  • 3
    Online Resource
    Online Resource
    Osteoprotection Through the Deletion of the Transcription Factor Rorβ in Mice
    Wiley ; 2018
    In:  Journal of Bone and Mineral Research Vol. 33, No. 4 ( 2018-04), p. 720-731
    Details
    In: Journal of Bone and Mineral Research, Wiley, Vol. 33, No. 4 ( 2018-04), p. 720-731
    Abstract: There is a clinical need to identify new molecular targets for the treatment of osteoporosis, particularly those that simultaneously inhibit bone resorption while stimulating bone formation. We have previously shown in overexpression studies that retinoic acid receptor‐related orphan receptor β (Rorβ) suppresses in vitro osteoblast differentiation. In addition, the expression of Rorβ is markedly increased in bone marrow–derived mesenchymal stromal cells with aging in both mice and humans. Here we establish a critical role for Rorβ in regulating bone metabolism using a combination of in vitro and in vivo studies. We used Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 gene editing to demonstrate that loss of Rorβ in osteoblasts enhances Wnt signaling, specifically through increased recruitment of β‐catenin to T‐cell factor/lymphoid enhancer factor (Tcf/Lef) DNA binding sites in the promoters of the Wnt target genes Tcf7 and Opg . This resulted in increased osteogenic gene expression and suppressed osteoclast formation through increased osteoprotegerin (OPG) secretion in Rorβ‐deficient cells. Consistent with our in vitro data, genetic deletion of Rorβ in both female and male mice resulted in preserved bone mass and microarchitecture with advancing age due to increased bone formation with a concomitant decrease in resorption. The improved skeletal phenotype in the Rorβ –/– mice was also associated with increased bone protein levels of TCF7 and OPG. These data demonstrate that loss of Rorβ has beneficial skeletal effects by increasing bone formation and decreasing bone resorption, at least in part through β‐catenin–dependent activation of the Wnt pathway. Thus, inhibition of Rorβ represents a novel approach to potentially prevent or reverse osteoporosis. © 2017 American Society for Bone and Mineral Research.
    Type of Medium: Online Resource
    ISSN: 0884-0431 , 1523-4681
    URL: Issue
    URL: Article
    DOI: 10.1002/jbmr.v33.4
    DOI: 10.1002/jbmr.3351
    RVK:
    XA 52230
    Language: English
    Publisher: Wiley
    Publication Date: 2018
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  • 4
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    Online Resource
    Development and Application of Mass Spectroscopy Assays for Nε-(1-Carboxymethyl)-L-Lysine and Pentosidine in Renal Failure and Diabetes
    Oxford University Press (OUP) ; 2020
    In:  The Journal of Applied Laboratory Medicine Vol. 5, No. 3 ( 2020-05-01), p. 558-568
    Details
    In: The Journal of Applied Laboratory Medicine, Oxford University Press (OUP), Vol. 5, No. 3 ( 2020-05-01), p. 558-568
    Abstract: Advanced glycation end products (AGEs) are formed via the nonenzymatic glycation of sugars with amino acids. Two AGEs, Nε-(1-carboxymethyl)-L-Lysine (CML) and pentosidine, have been observed to be elevated in subjects suffering from a multitude of chronic disease states, and accumulation of these compounds may be related to the pathophysiology of disease progression and aging. Methods We describe here the development and validation of a specific and reproducible LC-MS/MS method to quantify CML and pentosidine in human serum with lower limits of quantitation of 75 ng/mL and 5 ng/mL, respectively. The analyte calibration curve exhibited excellent linearity at a range of 0–10 900 ng/mL for CML and 0–800 ng/mL for pentosidine. High-low linearity of 5 serum pairs was assessed, with a mean recovery of 103% (range 94—116%) for CML, and 104% (range 97—116%) for pentosidine. Results Serum concentrations of CML and pentosidine were quantified in 30 control and 30 subjects with chronic renal insufficiency. A significant increase in both analytes was observed in renal failure compared to control subjects (2.1-fold and 8.4-fold, respectively; P  & lt; 0.001 for both). In a separate cohort of 49 control versus 95 subjects with type 2 diabetes mellitus (T2DM), serum CML but not serum pentosidine, was significantly elevated in the T2DM patients, and CML was also correlated with glycemic control, as assessed by hemoglobin A1c (r = 0.34, P  & lt; 0.001). Conclusions These mass spectroscopy-based assays for serum CML and pentosidine should be useful in accurately evaluating circulating levels of these key AGEs in various disease states.
    Type of Medium: Online Resource
    ISSN: 2576-9456 , 2475-7241
    URL: Article
    DOI: 10.1093/jalm/jfaa023
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
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