Browsing by Subject "Wnt/β-catenin"

Now showing 1 - 3 of 3
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    Mind Gaps and Bone Snaps: Exploring the Connection Between Alzheimer's Disease and Osteoporosis
    (Springer, 2024) Wang, Hannah S.; Karnik, Sonali J.; Margetts, Tyler J.; Plotkin, Lilian I.; Movila, Alexandru; Fehrenbacher, Jill C.; Kacena, Melissa A.; Oblak, Adrian L.; Orthopaedic Surgery, School of Medicine
    Purpose of review: This comprehensive review discusses the complex relationship between Alzheimer's disease (AD) and osteoporosis, two conditions that are prevalent in the aging population and result in adverse complications on quality of life. The purpose of this review is to succinctly elucidate the many commonalities between the two conditions, including shared pathways, inflammatory and oxidative mechanisms, and hormonal deficiencies. Recent findings: AD and osteoporosis share many aspects of their respective disease-defining pathophysiology. These commonalities include amyloid beta deposition, the Wnt/β-catenin signaling pathway, and estrogen deficiency. The shared mechanisms and risk factors associated with AD and osteoporosis result in a large percentage of patients that develop both diseases. Previous literature has established that the progression of AD increases the risk of sustaining a fracture. Recent findings demonstrate that the reverse may also be true, suggesting that a fracture early in the life course can predispose one to developing AD due to the activation of these shared mechanisms. The discovery of these commonalities further guides the development of novel therapeutics in which both conditions are targeted. This detailed review delves into the commonalities between AD and osteoporosis to uncover the shared players that bring these two seemingly unrelated conditions together. The discussion throughout this review ultimately posits that the occurrence of fractures and the mechanism behind fracture healing can predispose one to developing AD later on in life, similar to how AD patients are at an increased risk of developing fractures. By focusing on the shared mechanisms between AD and osteoporosis, one can better understand the conditions individually and as a unit, thus informing therapeutic approaches and further research. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews.
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    Muscle secreted factors enhance activation of the PI3K/Akt and β-catenin pathways in murine osteocytes
    (Elsevier, 2023) Lara-Castillo, N.; Masunaga, J.; Brotto, L.; Vallejo, J. A.; Javid, K.; Wacker, M. J.; Brotto, M.; Bonewald, L. F.; Johnson, M. L.; Medicine, School of Medicine
    Skeletal muscle and bone interact at the level of mechanical loading through the application of force by muscles to the skeleton and more recently focus has been placed on molecular/biochemical coupling of these two tissues. We sought to determine if muscle and muscle-derived factors were essential to the osteocyte response to loading. Botox® induced muscle paralysis was used to investigate the role of muscle contraction during in vivo tibia compression loading. 5-6 month-old female TOPGAL mice had their right hindlimb muscles surrounding the tibia injected with either BOTOX® or saline. At four days post injections when muscle paralysis peaked, the right tibia was subjected to a single session of in vivo compression loading at ∼2600 με. At 24 h post-load we observed a 2.5-fold increase in β-catenin signaling in osteocytes in the tibias of the saline injected mice, whereas loading of tibias from Botox® injected mice failed to active β-catenin signaling in osteocytes. This suggests that active muscle contraction produces a factor(s) that is necessary for or conditions the osteocyte's ability to respond to load. To further investigate the role of muscle derived factors, MLO-Y4 osteocyte-like cells and a luciferase based β-catenin reporter (TOPflash-MLO-Y4) cell line we developed were treated with conditioned media (CM) from C2C12 myoblasts (MB) and myotubes (MT) and ex vivo contracted Extensor Digitorum Longus (EDL) and Soleus (Sol) muscles under static or loading conditions using fluid flow shear stress (FFSS). 10 % C2C12 myotube CM, but not myoblast or NIH3T3 fibroblast cells CM, induced a rapid activation of the Akt signaling pathway, peaking at 15 min and returning to baseline by 1-2 h under static conditions. FFSS applied to MLO-Y4 cells for 2 h in the presence of 10 % MT-CM resulted in a 6-8 fold increase in pAkt compared to a 3-4 fold increase under control or when exposed to 10 % MB-CM. A similar response was observed in the presence of 10 % EDL-CM, but not in the presence of 10 % Sol-CM. TOPflash-MLO-Y4 cells were treated with 10 ng/ml Wnt3a in the presence or absence of MT-CM. While MT-CM resulted in a 2-fold activation and Wnt3a produced a 10-fold activation, the combination of MT-CM + Wnt3a resulted in a 25-fold activation of β-catenin signaling, implying a synergistic effect of factors in MT-CM with Wnt3a. These data provide clear evidence that specific muscles and myotubes produce factors that alter important signaling pathways involved in the response of osteocytes to mechanical load. These data strongly suggest that beyond mechanical loading there is a molecular coupling of muscle and bone.
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    Targeting of Deregulated Wnt/β-Catenin Signaling by PRI-724 and LGK974 Inhibitors in Germ Cell Tumor Cell Lines
    (MDPI, 2021-04-20) Schmidtova, Silvia; Kalavska, Katarina; Liskova, Veronika; Plava, Jana; Miklikova, Svetlana; Kucerova, Lucia; Matuskova, Miroslava; Rojikova, Lucia; Cierna, Zuzana; Rogozea, Adriana; Konig, Heiko; Albany, Costantine; Mego, Michal; Chovanec, Michal; Medicine, School of Medicine
    The majority of patients with testicular germ cell tumors (GCTs) can be cured with cisplatin-based chemotherapy. However, for a subset of patients present with cisplatin-refractory disease, which confers a poor prognosis, the treatment options are limited. Novel therapies are therefore urgently needed to improve outcomes in this challenging patient population. It has previously been shown that Wnt/β-catenin signaling is active in GCTs suggesting that its inhibitors LGK974 and PRI-724 may show promise in the management of cisplatin-refractory GCTs. We herein investigated whether LGK-974 and PRI-724 provide a treatment effect in cisplatin-resistant GCT cell lines. Taking a genoproteomic approach and utilizing xenograft models we found the increased level of β-catenin in 2 of 4 cisplatin-resistant (CisR) cell lines (TCam-2 CisR and NCCIT CisR) and the decreased level of β-catenin and cyclin D1 in cisplatin-resistant NTERA-2 CisR cell line. While the effect of treatment with LGK974 was limited or none, the NTERA-2 CisR exhibited the increased sensitivity to PRI-724 in comparison with parental cell line. Furthermore, the pro-apoptotic effect of PRI-724 was documented in all cell lines. Our data strongly suggests that a Wnt/β-catenin signaling is altered in cisplatin-resistant GCT cell lines and the inhibition with PRI-724 is effective in NTERA-2 CisR cells. Further evaluation of Wnt/β-catenin pathway inhibition in GCTs is therefore warranted.