| 1. |
- Movérare-Skrtic, Sofia, et al.
(författare)
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Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures.
- 2014
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 20:11, s. 1279-88
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Tidskriftsartikel (refereegranskat)abstract
- The WNT16 locus is a major determinant of cortical bone thickness and nonvertebral fracture risk in humans. The disability, mortality and costs caused by osteoporosis-induced nonvertebral fractures are enormous. We demonstrate here that Wnt16-deficient mice develop spontaneous fractures as a result of low cortical thickness and high cortical porosity. In contrast, trabecular bone volume is not altered in these mice. Mechanistic studies revealed that WNT16 is osteoblast derived and inhibits human and mouse osteoclastogenesis both directly by acting on osteoclast progenitors and indirectly by increasing expression of osteoprotegerin (Opg) in osteoblasts. The signaling pathway activated by WNT16 in osteoclast progenitors is noncanonical, whereas the pathway activated in osteoblasts is both canonical and noncanonical. Conditional Wnt16 inactivation revealed that osteoblast-lineage cells are the principal source of WNT16, and its targeted deletion in osteoblasts increases fracture susceptibility. Thus, osteoblast-derived WNT16 is a previously unreported key regulator of osteoclastogenesis and fracture susceptibility. These findings open new avenues for the specific prevention or treatment of nonvertebral fractures, a substantial unmet medical need.
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| 2. |
- Mushtaq, Irrum, et al.
(författare)
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Engineering electroactive and biocompatible tetra(aniline)-based terpolymers with tunable intrinsic antioxidant properties in vivo
- 2020
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Ingår i: Materials science & engineering. C, biomimetic materials, sensors and systems. - : Elsevier. - 0928-4931 .- 1873-0191. ; 108
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Tidskriftsartikel (refereegranskat)abstract
- Under different pathological conditions, high levels of reactive oxygen species (ROS) cause substantial damage to multiple organs. To counter these ROS levels in multiple organs, we have engineered highly potent novel terpolymers. We found that combination of FDA-approved polyethylene glycol, fumaric acid moieties and electroactive tetra(aniline) by varying the content of tetra(aniline) results into a novel drug composition with biologically active tunable intrinsic antioxidant properties. To test tunable intrinsic antioxidative properties of these engineered novel terpolymers, we used alloxan to induce diabetes in rats where ROS generation is known to be higher. The systemic administration of terpolymers to the diabetic rats showed strong electroactive antioxidant behavior which normalized ROS levels, enzymatic antioxidants including superoxide dismutase, catalase, but also reduced glutathione. As a proof-of-principle, we here show TANI based novel drug composition of terpolymers with tunable intrinsic antioxidant effects confirmed in multiple organs.
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| 3. |
- Velentza, Lilly, et al.
(författare)
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Humanin Treatment Protects Against Venetoclax-Induced Bone Growth Retardation in Ex Vivo Cultured Rat Bones
- 2024
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Ingår i: JOURNAL OF THE ENDOCRINE SOCIETY. - 2472-1972. ; 8:3
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Tidskriftsartikel (refereegranskat)abstract
- Context Recent preclinical studies reported that the BCL-2 inhibitor venetoclax can impair bone growth. A strategy to prevent such a side effect of this promising anticancer drug is highly desired. Earlier in vitro and in vivo studies suggested that the mitochondrial peptide humanin has the potential to prevent drug-induced growth impairment.Objective We hypothesized that co-treatment with the humanin analog HNG may prevent venetoclax-induced bone growth impairment.Methods Ex vivo studies were performed in fetal rat metatarsal bones and human growth plate samples cultured for 12 and 2 days, respectively, while in vivo studies were performed in young neuroblastoma mice being treated daily for 14 days. The treatment groups included venetoclax, HNG, venetoclax plus HNG, or vehicle. Bone growth was continuously monitored and at the end point, histomorphometric and immunohistochemical analyses were performed in fixed tissues.Results Venetoclax suppressed metatarsal bone growth and when combined with HNG, bone growth was rescued and all histological parameters affected by venetoclax monotherapy were normalized. Mechanistic studies showed that HNG downregulated the pro-apoptotic proteins Bax and p53 in cultured metatarsals and human growth plate tissues, respectively. The study in a neuroblastoma mouse model confirmed a growth-suppressive effect of venetoclax treatment. In this short-term in vivo study, no significant bone growth-rescuing effect could be verified when testing HNG at a single dose. We conclude that humanin dose-dependently protects ex vivo cultured metatarsal bones from venetoclax-induced bone growth impairment by restoring the growth plate microstructure.
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| 4. |
- Zaman, Farasat
(författare)
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Effects of chemotherapy on bone growth and chondrocyte cell death signaling
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Glucocorticoids (GCs) are widely used in both children and adults to treat common inflammatory diseases, including asthma, rheumatoid arthritis, ulcerative colitis and Crohn’s disease. However, a multitude of undesired side effects have been reported in patients being treated with GCs, such as osteoporosis, obesity, metabolic disturbances, myopathy and decreased linear bone growth (in children). Dexamethasone, a widely used GC, often causes bone growth impairment as an undesired side-effect in treated children. This observation is supported by experimental data showing that dexamethasone alters proliferation/differentiation and abnormally triggers apoptosis within the growth plate, which may play a key role in the pathophysiology of dexamethasone-induced growth retardation. By investigating these mechanisms, we found that dexamethasone activates caspase-8, -9 and -3 in proliferative chondrocytes. In addition, the Akt-PI3K signaling pathway, which plays a key role in the survival and proliferation of growth plate chondrocytes, is also impaired due to dexamethasone-induced inhibition of Akt phosphorylation. The observation of caspase-9 activation from these studies suggests that an intrinsic apoptotic pathway is also activated in chondrocytes. Therefore, we hypothesized that Bax, a pro-apoptotic member of the Bcl-2 family that is known to regulate intrinsic apoptosis, may play a key role in dexamethasone-induced retardation of bone growth. In chondrocytes, dexamethasone induced conformational changes in Bax, dissipation of the mitochondrial membrane potential and resulted in the release of cytochrome c. Further, Bax-siRNA prevented chondrocytes from undergoing apoptosis. Bax activation was also observed in human growth plate cartilage specimens cultured ex vivo in the presence of dexamethasone. Finally, we observed that Bax-deficient mice were protected from dexamethasone-induced bone growth retardation. Collectively, our data reveal a novel role for Bax in dexamethasone-induced bone growth retardation and impaired bone formation. These findings highlight the possibility for new therapeutic approaches to prevent GC-induced growth failure by specifically targeting Bax (Paper- I, II). Proteasome inhibitors (PIs) such as MG262 and bortezomib are a novel class of anticancer drugs. Bortezomib has recently been introduced clinically to treat multiple myeloma and is under clinical trials in children to treat various cancers. Here we show for the first time that systemic administration of PIs specifically impairs the ubiquitin/proteasome system (UPS) in growth plate chondrocytes. Importantly, we found that young mice display severe growth retardation during treatment, as well as 45 days after the cessation of treatment, with clinically relevant amounts of PIs. Dysfunction of the UPS was also accompanied by the induction of apoptosis (p53-, apoptosis-inducing factor (AIF)- and Bax-mediated apoptosis) of stem-like and proliferative chondrocytes in the growth plate. We also provide evidence that AIF serves as a direct target protein for ubiquitin, thus explaining its prominent upregulation upon proteasome inhibition. Suppression of p53 or AIF expression with siRNA partially rescued chondrocytes from PI-induced apoptosis (35 and 41%, respectively). These findings show that PIs may selectively target essential cell populations in the growth plate, causing significant growth failure, and our results could have important implications for the use of PIs in the treatment of childhood cancer (Paper-III, IV).
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| 6. |
- Zhang, Zhengpei, et al.
(författare)
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Micromechanical Loading Studies in Ex Vivo Cultured Embryonic Rat Bones Enabled by a Newly Developed Portable Loading Device
- 2023
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Ingår i: Annals of Biomedical Engineering. - : Springer Nature. - 0090-6964 .- 1573-9686. ; 51:10, s. 2229-2236
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Tidskriftsartikel (refereegranskat)abstract
- Mechanical loading has been described as having the potential to affect bone growth. In order to experimentally study the potential clinical applications of mechanical loading as a novel treatment to locally modulate bone growth, there is a need to develop a portable mechanical loading device enabling studies in small bones. Existing devices are bulky and challenging to transfer within and between laboratories and animal facilities, and they do not offer user-friendly mechanical testing across both ex vivo cultured small bones and in vivo animal models. To address this, we developed a portable loading device comprised of a linear actuator fixed within a stainless-steel frame equipped with suitable structures and interfaces. The actuator, along with the supplied control system, can achieve high-precision force control within the desired force and frequency range, allowing various load application scenarios. To validate the functionality of this new device, proof-of-concept studies were performed in ex vivo cultured rat bones of varying sizes. First, very small fetal metatarsal bones were microdissected and exposed to 0.4 N loading applied at 0.77 Hz for 30 s. When bone lengths were measured after 5 days in culture, loaded bones had grown less than unloaded controls (p < 0.05). Next, fetal rat femur bones were periodically exposed to 0.4 N loading at 0.77 Hz while being cultured ex vivo for 12 days. Interestingly, this loading regimen had the opposite effect on bone growth, i.e., loaded femur bones grew significantly more than unloaded controls (p < 0.001). These findings suggest that complex relationships between longitudinal bone growth and mechanical loading can be determined using this device. We conclude that our new portable mechanical loading device allows experimental studies in small bones of varying sizes, which may facilitate further preclinical studies exploring the potential clinical applications of mechanical loading.
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