Browsing by Author "Jähn, Katharina"

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    Crosstalk between MLO-Y4 osteocytes and C2C12 muscle cells is mediated by the Wnt/β-catenin pathway
    (Wiley, 2017) Huang, Jian; Romero-Suarez, Sandra; Lara, Nuria; Mo, Chenglin; Kaja, Simon; Brotto, Leticia; Dallas, Sarah L.; Johnson, Mark L.; Jähn, Katharina; Bonewald, Lynda F.; Brotto, Marco; Department of Anatomy and Cell Biology, School of Medicine
    We examined the effects of osteocyte secreted factors on myogenesis and muscle function. MLO-Y4 osteocyte-like cell conditioned media (CM) (10%) increased ex vivo soleus muscle contractile force by ∼25%. MLO-Y4 and primary osteocyte CM (1-10%) stimulated myogenic differentiation of C2C12 myoblasts, but 10% osteoblast CMs did not enhance C2C12 cell differentiation. Since WNT3a and WNT1 are secreted by osteocytes, and the expression level of Wnt3a is increased in MLO-Y4 cells by fluid flow shear stress, both were compared, showing WNT3a more potent than WNT1 in inducing myogenesis. Treatment of C2C12 myoblasts with WNT3a at concentrations as low as 0.5ng/mL mirrored the effects of both primary osteocyte and MLO-Y4 CM by inducing nuclear translocation of β-catenin with myogenic differentiation, suggesting that Wnts might be potential factors secreted by osteocytes that signal to muscle cells. Knocking down Wnt3a in MLO-Y4 osteocytes inhibited the effect of CM on C2C12 myogenic differentiation. Sclerostin (100ng/mL) inhibited both the effects of MLO-Y4 CM and WNT3a on C2C12 cell differentiation. RT-PCR array results supported the activation of the Wnt/β-catenin pathway by MLO-Y4 CM and WNT3a. These results were confirmed by qPCR showing up-regulation of myogenic markers and two Wnt/β-catenin downstream genes, Numb and Flh1. We postulated that MLO-Y4 CM/WNT3a could modulate intracellular calcium homeostasis as the trigger mechanism for the enhanced myogenesis and contractile force. MLO-Y4 CM and WNT3a increased caffeine-induced Ca2+ release from the sarcoplasmic reticulum (SR) of C2C12 myotubes and the expression of genes directly associated with intracellular Ca2+ signaling and homeostasis. Together, these data show that in vitro and ex vivo, osteocytes can stimulate myogenesis and enhance muscle contractile function and suggest that Wnts could be mediators of bone to muscle signaling, likely via modulation of intracellular Ca2+ signaling and the Wnt/ β-Catenin pathway.
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    Intramedullary Mg2Ag nails augment callus formation during fracture healing in mice
    (Elsevier, 2016-05) Jähn, Katharina; Saito, Hiroaki; Taipaleenmäki, Hanna; Gasser, Andreas; Hort, Norbert; Feyerabend, Frank; Schlüter, Hartmut; Rueger, Johannes M.; Lehmann, Wolfgang; Willumeit-Römer, Regine; Hesse, Eric; Department of Anatomy & Cell Biology, IU School of Medicine
    Intramedullary stabilization is frequently used to treat long bone fractures. Implants usually remain unless complications arise. Since implant removal can become technically very challenging with the potential to cause further tissue damage, biodegradable materials are emerging as alternative options. Magnesium (Mg)-based biodegradable implants have a controllable degradation rate and good tissue compatibility, which makes them attractive for musculoskeletal research. Here we report for the first time the implantation of intramedullary nails made of an Mg alloy containing 2% silver (Mg2Ag) into intact and fractured femora of mice. Prior in vitro analyses revealed an inhibitory effect of Mg2Ag degradation products on osteoclast differentiation and function with no impair of osteoblast function. In vivo, Mg2Ag implants degraded under non-fracture and fracture conditions within 210 days and 133 days, respectively. During fracture repair, osteoblast function and subsequent bone formation were enhanced, while osteoclast activity and bone resorption were decreased, leading to an augmented callus formation. We observed a widening of the femoral shaft under steady state and regenerating conditions, which was at least in part due to an uncoupled bone remodeling. However, Mg2Ag implants did not cause any systemic adverse effects. These data suggest that Mg2Ag implants might be promising for intramedullary fixation of long bone fractures, a novel concept that has to be further investigated in future studies.
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    TG-interacting factor 1 (Tgif1)-deficiency attenuates bone remodeling and blunts the anabolic response to parathyroid hormone
    (Nature Research, 2019-03-22) Saito, Hiroaki; Gasser, Andreas; Bolamperti, Simona; Maeda, Miki; Matthies, Levi; Jähn, Katharina; Long, Courtney L.; Schlüter, Hartmut; Kwiatkowski, Marcel; Saini, Vaibhav; Pajevic, Paola Divieti; Bellido, Teresita; Wijnen, Andre J. van; Mohammad, Khalid S.; Guise, Theresa A.; Taipaleenmäki, Hanna; Hesse, Eric; Anatomy and Cell Biology, School of Medicine
    Osteoporosis is caused by increased bone resorption and decreased bone formation. Intermittent administration of a fragment of Parathyroid hormone (PTH) activates osteoblast-mediated bone formation and is used in patients with severe osteoporosis. However, the mechanisms by which PTH elicits its anabolic effect are not fully elucidated. Here we show that the absence of the homeodomain protein TG-interacting factor 1 (Tgif1) impairs osteoblast differentiation and activity, leading to a reduced bone formation. Deletion of Tgif1 in osteoblasts and osteocytes decreases bone resorption due to an increased secretion of Semaphorin 3E (Sema3E), an osteoclast-inhibiting factor. Tgif1 is a PTH target gene and PTH treatment failed to increase bone formation and bone mass in Tgif1-deficient mice. Thus, our study identifies Tgif1 as a novel regulator of bone remodeling and an essential component of the PTH anabolic action. These insights contribute to a better understanding of bone metabolism and the anabolic function of PTH.
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    β-aminoisobutyric Acid, L-BAIBA, Is a Muscle-Derived Osteocyte Survival Factor
    (Cell Press, 2018-02-06) Kitase, Yukiko; Vallejo, Julian A.; Gutheil, William; Vemula, Harika; Jähn, Katharina; Yi, Jianxun; Zhou, Jingsong; Brotto, Marco; Bonewald, Lynda F.; Anatomy and Cell Biology, School of Medicine
    Exercise has beneficial effects on metabolism and on tissues. The exercise-induced muscle factor β-aminoisobutyric acid (BAIBA) plays a critical role in the browning of white fat and in insulin resistance. Here we show another function for BAIBA, that of a bone-protective factor that prevents osteocyte cell death induced by reactive oxygen species (ROS). L-BAIBA was as or more protective than estrogen or N-acetyl cysteine, signaling through the Mas-Related G Protein-Coupled Receptor Type D (MRGPRD) to prevent the breakdown of mitochondria due to ROS. BAIBA supplied in drinking water prevented bone loss and loss of muscle function in the murine hindlimb unloading model, a model of osteocyte apoptosis. The protective effect of BAIBA was lost with age, not due to loss of the muscle capacity to produce BAIBA but likely to reduced Mrgprd expression with aging. This has implications for understanding the attenuated effect of exercise on bone with aging.,