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Amirhosseini, Mehdi
Publications (3 of 3) Show all publications
Amirhosseini, M. (2019). Aseptic Loosening of Orthopedic Implants: Osteoclastogenesis Regulation and Potential Therapeutics. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Aseptic Loosening of Orthopedic Implants: Osteoclastogenesis Regulation and Potential Therapeutics
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Aseptic loosening is the main cause of failure of orthopedic prostheses. With no pharmaceuticals to prevent or mitigate periprosthetic bone degradation, a surgery to replace the loose implant with a new one is the only choice to restore patients’ function. Most studies on mechanisms for aseptic loosening investigate wear debris particle-induced osteolysis. However, pathological loading conditions around unstable implants can also trigger osteoclast differentiation and bone loss.

In the first study, global gene expression changes induced by mechanical instability of implants, and by titanium particles were compared in a validated rat model for aseptic loosening. Microarray analysis showed that similar signaling pathways and gene expression patterns are involved in particle- and instability-induced periprosthetic osteolysis with an early onset innate immune response as a hallmark of osteolysis induced by mechanical instability.

Further, effects of potential therapeutics on restriction of excessive osteoclast differentiation were evaluated. Wnt signaling pathway is known to regulate bone remodeling. In the second study, effects of inactivation of glycogen synthase kinase 3 beta (GSK-3β), a negative regulator of canonical Wnt signaling, on instability-induced periprosthetic osteolysis were examined using our rat model for aseptic loosening. Inhibition of GSK-3β led to a decrease in osteoclast numbers in the periprosthetic bone tissue exposed to mechanical instability while osteoblast perimeter showed an increase. This was accompanied by higher bone volume fraction (BV/TV) in animals treated with the GSK-3β inhibitor.

In the third study, potential beneficial effects of two selective inhibitors of cyclindependent kinase 8/19 (CDK8/19) on bone tissue were evaluated. CDK8/19 is a Mediator complex-associated transcriptional regulator involved in several signaling pathways. CDK8/19 inhibitors, mainly under investigation as treatments for tumors, are reported to enhance osteoblast differentiation and bone formation. We show in this study, for the first time, that inhibition of CDK8/19 led to marked suppression of osteoclast differentiation from bone marrow macrophages in vitro through disruption of the RANK signaling. In mouse primary osteoblasts downregulation of osteopontin mRNA, a negative regulator of mineralization, together with increased alkaline phosphatase activity and calcium deposition indicated that osteoblast mineralization was promoted by CDK8/19 inhibition. Moreover, local administration of a CDK8/19 inhibitor promoted cancellous bone regeneration in a rat model for bone healing.

These studies contribute to better understanding of mechanisms behind mechanical instability-induced periprosthetic osteolysis and propose potential therapeutics to restrict bone loss with effects on both osteoclasts and osteoblasts.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2019. p. 41
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1634
National Category
Cell Biology Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-154926 (URN)10.3384/diss.diva-154926 (DOI)9789176852385 (ISBN)
Public defence
2019-03-26, Belladonna, Campus US, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2019-03-05 Created: 2019-03-05 Last updated: 2019-05-24Bibliographically approved
Amirhosseini, M., Bernhardsson, M., Lång, P., Andersson, G., Flygare, J. & Fahlgren, A. (2019). Cyclin-dependent kinase 8/19 inhibition suppresses osteoclastogenesis by downregulating RANK and promotes osteoblast mineralization and cancellous bone healing.. Journal of Cellular Physiology, 234(9), 16503-16516
Open this publication in new window or tab >>Cyclin-dependent kinase 8/19 inhibition suppresses osteoclastogenesis by downregulating RANK and promotes osteoblast mineralization and cancellous bone healing.
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2019 (English)In: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 234, no 9, p. 16503-16516Article in journal (Refereed) Published
Abstract [en]

Cyclin-dependent kinase 8 (CDK8) is a mediator complex-associated transcriptional regulator that acts depending on context and cell type. While primarily under investigation as potential cancer therapeutics, some inhibitors of CDK8-and its paralog CDK19-have been reported to affect the osteoblast lineage and bone formation. This study investigated the effects of two selective CDK8/19 inhibitors on osteoclastogenesis and osteoblasts in vitro, and further evaluated how local treatment with a CDK8/19 inhibitor affects cancellous bone healing in rats. CDK8/19 inhibitors did not alter the proliferation of neither mouse bone marrow-derived macrophages (BMMs) nor primary mouse osteoblasts. Receptor activator of nuclear factor κΒ (NF-κB) ligand (RANKL)-induced osteoclastogenesis from mouse BMMs was suppressed markedly by inhibition of CDK8/19, concomitant with reduced tartrate-resistant acid phosphatase (TRAP) activity and C-terminal telopeptide of type I collagen levels. This was accompanied by downregulation of PU.1, RANK, NF-κB, nuclear factor of activated T-cells 1 (NFATc1), dendritic cell-specific transmembrane protein (DC-STAMP), TRAP, and cathepsin K in RANKL-stimulated BMMs. Downregulating RANK and its downstream signaling in osteoclast precursors enforce CDK8/19 inhibitors as anticatabolic agents to impede excessive osteoclastogenesis. In mouse primary osteoblasts, CDK8/19 inhibition did not affect differentiation but enhanced osteoblast mineralization by promoting alkaline phosphatase activity and downregulating osteopontin, a negative regulator of mineralization. In rat tibiae, a CDK8/19 inhibitor administered locally promoted cancellous bone regeneration. Our data indicate that inhibitors of CDK8/19 have the potential to develop into therapeutics to restrict osteolysis and enhance bone regeneration.

Keywords
CDK8, RANK, osteoblasts, osteoclasts
National Category
Cell and Molecular Biology Medicinal Chemistry
Identifiers
urn:nbn:se:liu:diva-154927 (URN)10.1002/jcp.28321 (DOI)000470174200186 ()30793301 (PubMedID)
Note

Funding agencies: Vetenskapsradet [521-2013-2593, 2016-06097, K2015-99x-10363-23-4, 2016-01822]; Swedish Research Council

Available from: 2019-03-05 Created: 2019-03-05 Last updated: 2019-07-03
Amirhosseini, M., Andersson, G., Aspenberg, P. & Fahlgren, A. (2017). Mechanical instability and titanium particles induce similar transcriptomic changes in a rat model for periprosthetic osteolysis and aseptic loosening. Bone Reports, 7, 17-25
Open this publication in new window or tab >>Mechanical instability and titanium particles induce similar transcriptomic changes in a rat model for periprosthetic osteolysis and aseptic loosening
2017 (English)In: Bone Reports, ISSN 2352-1872, Vol. 7, p. 17-25Article in journal (Refereed) Published
Abstract [en]

Wear debris particles released from prosthetic bearing surfaces and mechanical instability of implants are two main causes of periprosthetic osteolysis. While particle-induced loosening has been studied extensively, mechanisms through which mechanical factors lead to implant loosening have been less investigated. This study compares the transcriptional profiles associated with osteolysis in a rat model for aseptic loosening, induced by either mechanical instability or titanium particles. Rats were exposed to mechanical instability or titanium particles. After 15 min, 3, 48 or 120 h from start of the stimulation, gene expression changes in periprosthetic bone tissue was determined by microarray analysis. Microarray data were analyzed by PANTHER Gene List Analysis tool and Ingenuity Pathway Analysis (IPA). Both types of osteolytic stimulation led to gene regulation in comparison to unstimulated controls after 3, 48 or 120 h. However, when mechanical instability was compared to titanium particles, no gene showed a statistically significant difference (fold change = ± 1.5 and adjusted p-value = 0.05) at any time point. There was a remarkable similarity in numbers and functional classification of regulated genes. Pathway analysis showed several inflammatory pathways activated by both stimuli, including Acute Phase Response signaling, IL-6 signaling and Oncostatin M signaling. Quantitative PCR confirmed the changes in expression of key genes involved in osteolysis observed by global transcriptomics. Inflammatory mediators including interleukin (IL)-6, IL-1ß, chemokine (C-C motif) ligand (CCL)2, prostaglandin-endoperoxide synthase (Ptgs)2 and leukemia inhibitory factor (LIF) showed strong upregulation, as assessed by both microarray and qPCR. By investigating genome-wide expression changes we show that, despite the different nature of mechanical implant instability and titanium particles, osteolysis seems to be induced through similar biological and signaling pathways in this rat model for aseptic loosening. Pathways associated to the innate inflammatory response appear to be a major driver for osteolysis. Our findings implicate early restriction of inflammation to be critical to prevent or mitigate osteolysis and aseptic loosening of orthopedic implants.

Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
Aseptic loosening; Implant; Instability; Microarray; Wear debris
National Category
Cell and Molecular Biology Orthopaedics
Identifiers
urn:nbn:se:liu:diva-146297 (URN)10.1016/j.bonr.2017.07.003 (DOI)28795083 (PubMedID)
Available from: 2018-04-07 Created: 2018-04-07 Last updated: 2019-03-08
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