Browsing by Author "Himes, Evan"

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    Alterations to maternal cortical and trabecular bone in multiparous middle-aged mice
    (Hylonome, 2017-11) Gu, Alex; Sellamuthu, Rajendran; Himes, Evan; Childress, Paul J.; Pelus, Louis M.; Orschell, Christie M.; Kacena, Melissa A.; Orthopaedic Surgery, School of Medicine
    Objectives: During the reproductive cycle, altered calcium homeostasis is observed due to variable demand for mineral requirements. This results in increased bone resorption during the time period leading up to parturition and subsequent lactation. During lactation, women will lose 1-3% of bone mineral density per month, which is comparable to the loss experienced on an annual basis post-menopausal. The purpose of this study was to determine the effect of parity on bone formation in middle-aged mice. Methods: Mice were mated and grouped by number of parity and compared with age matched nulliparous controls. Measurements were taken of femoral trabecular and cortical bone. Calcium, protein and alkaline phosphatase levels were also measured. Results: An increase in trabecular bone mineral density was observed when comparing mice that had undergone parity once to the nulliparous control. An overall decrease in trabecular bone mineral density was observed as parity increased from 1 to 5 pregnancies. No alteration was seen in cortical bone formation. No difference was observed when calcium, protein and alkaline phosphatase levels were assessed. Conclusions: This study demonstrates that number of parity has an impact on trabecular bone formation in middle-aged mice, with substantial changes in bone density seen among the parous groups.
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    Megakaryocyte and Osteoblast Interactions Modulate Bone Mass and Hematopoiesis
    (Mary Ann Liebert, 2018-05-15) Alvarez, Marta B.; Xu, LinLin; Childress, Paul J.; Maupin, Kevin A.; Mohamad, Safa F.; Chitteti, Brahmananda R.; Himes, Evan; Olivos, David J.; Cheng, Ying-Hua; Conway, Simon J.; Srour, Edward F.; Kacena, Melissa A.; Orthopaedic Surgery, School of Medicine
    Emerging evidence demonstrates that megakaryocytes (MK) play key roles in regulating skeletal homeostasis and hematopoiesis. To test if the loss of MK negatively impacts osteoblastogenesis and hematopoiesis, we generated conditional knockout mice where Mpl, the receptor for the main MK growth factor, thrombopoietin, was deleted specifically in MK (Mplf/f;PF4cre). Unexpectedly, at 12 weeks of age, these mice exhibited a 10-fold increase in platelets, a significant expansion of hematopoietic/mesenchymal precursors, and a remarkable 20-fold increase in femoral midshaft bone volume. We then investigated whether MK support hematopoietic stem cell (HSC) function through the interaction of MK with osteoblasts (OB). LSK cells (Lin-Sca1+CD117+, enriched HSC population) were co-cultured with OB+MK for 1 week (1wk OB+MK+LSK) or OB alone (1wk OB+LSK). A significant increase in colony-forming units was observed with cells from 1wk OB+MK cultures. Competitive repopulation studies demonstrated significantly higher engraftment in mice transplanted with cells from 1wk OB+MK+LSK cultures compared to 1wk OB+LSK or LSK cultured alone for 1 week. Furthermore, single-cell expression analysis of OB cultured±MK revealed adiponectin as the most significantly upregulated MK-induced gene, which is required for optimal long-term hematopoietic reconstitution. Understanding the interactions between MK, OB, and HSC can inform the development of novel treatments to enhance both HSC recovery following myelosuppressive injuries, as well as bone loss diseases, such as osteoporosis.
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    The role of STAT3 in osteoclast mediated bone resorption
    (2014-08-01) Himes, Evan; Li, Jiliang; Yost, Robert; Kacena, Melissa A.; Atkinson, Simon
    Signal Transducer and Activator of Transcription 3 (STAT3) is known to be related to bone metabolism. Mutation of STAT3 causes a rare disorder in which serum levels of IgE are elevated. This causes various skeletal problems similar to osteoporosis. To examine the effect of STAT3 in the osteoclast, we obtained two osteoclast specific STAT3 knockout mouse models: one using the CTSK promoter to drive Cre recombinase and another using a TRAP promoter. Examination of these mice at 8 weeks of age revealed a decreased trabecular bone volume in CTSK specific STAT3 knockout mice along with a slight decrease in osteoclast number in both CTSK and TRAP specific STAT3 knockout females. We also noticed changes in bone mineral density and bone mechanical strength in females. These data suggest that STAT3 plays a part in the function of the osteoclast.
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    Selective inactivation of Stat3 in osteoclasts affect bone mass differently in female and male mice
    (Office of the Vice Chancellor for Research, 2013-04-05) Himes, Evan; Zhou, Hongkang; Li, Jiliang
    Signal Transducer and Activator of Transcription 3 (Stat3) is activated by the binding of various cytokines to their receptors, such as IL-6. Previous studies have revealed that conditional knockouts of Stat3 in osteoblasts and osteocytes cause a decrease in bone mineral density and strength. To study the role of Stat3 in osteoclasts, osteoclast- specific knockout mice were created using cre-lox recombination. Bone mineral density (BMD) and bone mineral content (BMC) were calculated for femurs and the fourth lumbar vertebra (L4) of 8 weeks old mice. Analysis revealed a decrease in BMD of femurs of osteoclast-selective Stat3 knockout (KOOc-Stat3) mice compared to their littermate control (p<0.05). There was also a decrease in BMC of the femurs of KOOc-Stat3 mice compared to the littermate controls (p<0.05). Analysis of μCT data from trabecular bone in the distal femur showed significant decreases in trabecular number and bone volume/tissue volume in both male and female KOOc-Stat3 mice. Trabecular separation was increased in male and female KOOc-Stat3 mice. Bone histomorphometry at the distal femur revealed a significant decrease in bone formation rate in males and females KOOc-Stat3 mice compared to the littermate controls. Osteoclast number identified by tartrate resistant acid phosphatase (TRAP) stain in female KOOc-Stat3 mice was significantly deficient from their control. These data suggest that inactivation of Stat3 in osteoclasts influences bone metabolism through both osteoblasts and osteoclasts. Knockout of Stat3 in either cell type leads to decreases in bone strength, making Stat3 a good drug target for treatment of diseases such as osteoporosis.