Browsing by Author "Department of Anatomy & Cell Biology, School of Medicine"

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    Age-related changes in structure and extracellular matrix protein expression levels in rat tendons
    (Springer, Part of Springer Science+Business Media, 2013-12) Kostrominova, Tatiana Y.; Brooks, Susan V.; Department of Anatomy & Cell Biology, School of Medicine
    The musculoskeletal system (muscle–tendon–bone) demonstrates numerous age-related changes, with modifications in tendons the least well studied, although increased predisposition to tendinopathy and rupture have been reported. In order to gain insights into the basis of age-associated increase in tendon injuries, we compared Achilles and tibialis anterior tendons and myotendinous junctions (MTJs) from 3- to 5- and 22- to 25-month-old rats for underlying structure and composition. Significant decreases were observed by qRT-PCR for collagen I, III, and V mRNA expression in tendons of old rats, but immunostaining detected no apparent differences in collagen I and V expression on the protein level. Tendons of old compared with young rats had decreased mRNA expression levels of proteoglycan 4 (PRG4) and elastin (Eln), but no differences in the mRNA expression of connective tissue growth factor, TGF-beta 1, or stromal cell-derived factor 1. For PRG4, immunostaining showed good correlation with qRT-PCR results. This is the first study to show reductions in PRG4 in tendons and MTJs of old rats. Decreased PRG4 expression in tendons could result in increased tendon stiffness and may be associated with decreased activity in the elderly. The diminished collagen mRNA expression in combination with decreased PRG4 and Eln mRNA expression may be associated with increased risk of tendon injury with aging.
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    Axotomy-induced target disconnection promotes an additional death mechanism involved in motoneuron degeneration in amyotrophic lateral sclerosis transgenic mice
    (Wiley, 2014-07) Haulcomb, Melissa M.; Mesnard, Nichole A.; Batka, Richard J.; Alexander, Thomas D.; Sanders, Virginia M.; Jones, Kathryn J.; Department of Anatomy & Cell Biology, School of Medicine
    The target disconnection theory of amyotrophic lateral sclerosis (ALS) pathogenesis suggests that disease onset is initiated by a peripheral pathological event resulting in neuromuscular junction loss and motoneuron (MN) degeneration. Presymptomatic mSOD1(G93A) mouse facial MN (FMN) are more susceptible to axotomy-induced cell death than wild-type (WT) FMN, which suggests additional CNS pathology. We have previously determined that the mSOD1 molecular response to facial nerve axotomy is phenotypically regenerative and indistinguishable from WT, whereas the surrounding microenvironment shows significant dysregulation in the mSOD1 facial nucleus. To elucidate the mechanisms underlying the enhanced mSOD1 FMN loss after axotomy, we superimposed the facial nerve axotomy model on presymptomatic mSOD1 mice and investigated gene expression for death receptor pathways after target disconnection by axotomy vs. disease progression. We determined that the TNFR1 death receptor pathway is involved in axotomy-induced FMN death in WT and is partially responsible for the mSOD1 FMN death. In contrast, an inherent mSOD1 CNS pathology resulted in a suppressed glial reaction and an upregulation in the Fas death pathway after target disconnection. We propose that the dysregulated mSOD1 glia fail to provide support the injured MN, leading to Fas-induced FMN death. Finally, we demonstrate that, during disease progression, the mSOD1 facial nucleus displays target disconnection-induced gene expression changes that mirror those induced by axotomy. This validates the use of axotomy as an investigative tool in understanding the role of peripheral target disconnection in the pathogenesis of ALS.
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    Contrasting histopathology and crystal deposits in kidneys of idiopathic stone formers who produce hydroxy apatite, brushite, or calcium oxalate stones
    (Wiley, 2014-04) Evan, Andrew P.; Lingeman, James E.; Worcester, Elaine M.; Sommer, Andre J.; Phillips, Carrie L.; Williams, James C.; Coe, Fredric L.; Department of Anatomy & Cell Biology, School of Medicine
    Our previous work has shown that stone formers who form calcium phosphate (CaP) stones that contain any brushite (BRSF) have a distinctive renal histopathology and surgical anatomy when compared with idiopathic calcium oxalate stone formers (ICSF). Here we report on another group of idiopathic CaP stone formers, those forming stone containing primarily hydroxyapatite, in order to clarify in what ways their pathology differs from BRSF and ICSF. Eleven hydroxyapatite stone formers (HASF) (2 males, 9 females) were studied using intra-operative digital photography and biopsy of papillary and cortical regions to measure tissue changes associated with stone formation. Our main finding is that HASF and BRSF differ significantly from each other and that both differ greatly from ICSF. Both BRSF and ICSF patients have significant levels of Randall's plaque compared with HASF. Intra-tubular deposit number is greater in HASF than BRSF and nonexistent in ICSF while deposit size is smaller in HASF than BRSF. Cortical pathology is distinctly greater in BRSF than HASF. Four attached stones were observed in HASF, three in 25 BRSF and 5-10 per ICSF patient. HASF and BRSF differ clinically in that both have higher average urine pH, supersaturation of CaP, and calcium excretion than ICSF. Our work suggests that HASF and BRSF are two distinct and separate diseases and both differ greatly from ICSF.
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    High Bone Mass in Mice Lacking Cx37 Due to Defective Osteoclast Differentiation
    (American Society for Biochemistry and Molecular Biology, 2014-02) Pacheco-Costa, Rafael; Hassan, Iraj; Reginato, Rejane D.; Davis, Hannah M.; Bruzzaniti, Angela; Allen, Matthew R.; Plotkin, Lilian I.; Department of Anatomy & Cell Biology, School of Medicine
    Connexin (Cx) proteins are essential for cell differentiation, function and survival in all tissues with Cx43 being the most studied in bone. We now report that Cx37, another member of the connexin family of proteins, is expressed in osteoclasts, osteoblasts and osteocytes. Mice with global deletion of Cx37 (Cx37-/-) exhibit higher BMD, cancellous bone volume, and mechanical strength compared to wild type littermates. Osteoclast number and surface are significantly lower in bone of Cx37-/- mice. In contrast, osteoblast number and surface and bone formation rate in bones from Cx37-/- mice are unchanged. Moreover, markers of osteoblast activity ex vivo and in vivo are similar to those of Cx37+/+ littermates. sRANKL/M-CSF treatment of non-adherent Cx37-/- bone marrow cells rendered a 5-fold lower level of osteoclast differentiation compared to Cx37+/+ cell cultures. Further, Cx37-/- osteoclasts are smaller and have fewer nuclei per cell. Expression of RANK, TRAP, cathepsin K, calcitonin receptor, MMP9, NFATc1, DCSTAMP, ATP6v0d1 and CD44, markers of osteoclast number, fusion or activity, is lower in Cx37-/- osteoclasts compared to controls. In addition, non-adherent bone marrow cells from Cx37-/- mice exhibit higher levels of markers for osteoclast precursors, suggesting altered osteoclast differentiation. The reduction of osteoclast differentiation is associated with activation of Notch signaling. We conclude that Cx37 is required for osteoclast differentiation and fusion and its absence leads to arrested osteoclast maturation and high bone mass in mice. These findings demonstrate a previously unrecognized role of Cx37 in bone homeostasis that is not compensated for by Cx43 in vivo.