Publications by authors named "Yoko Hosaka"

10 Publications

  • Page 1 of 1

Irreducible Chronic Volar Dislocation of the Distal Radioulnar Joint After Surgery for Distal Radius Fracture: A Case Report.

JBJS Case Connect 2021 06 11;11(2). Epub 2021 Jun 11.

Department of Orthopaedic Surgery, Mitsui Memorial Hospital, Chiyoda-ku, Tokyo, Japan.

Case: We report a case of irreducible chronic volar dislocation of the distal radioulnar joint (DRUJ) after surgery for distal radius fracture. The patient underwent volar locking plate fixation for distal radius fracture. Despite the satisfactory alignment of the distal radius, irreducible volar dislocation of the DRUJ was discovered at 5 weeks after the initial surgery. DRUJ reconstruction at 9 weeks after injury using the Adams-Berger procedure resulted in a stable and functional DRUJ and wrist.

Conclusion: To prevent postoperative DRUJ instability or dislocation, the DRUJ should be evaluated for stability immediately after fracture fixation.
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http://dx.doi.org/10.2106/JBJS.CC.20.00838DOI Listing
June 2021

Alteration of gait parameters in a mouse model of surgically induced knee osteoarthritis.

J Orthop Surg (Hong Kong) 2018 May-Aug;26(2):2309499018768017

1 Sensory & Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Purpose: Joint pain is the most common symptom of osteoarthritis (OA); however, its mechanism remains unclarified. The present study investigated hindlimb motion during locomotion on the treadmill using a three-dimensional (3D) motion analysis system with high-speed cameras to evaluate whether this method can be used as an indication of joint pain in a mouse model of surgically induced OA.

Methods: We resected the medial meniscus and medial collateral ligament in 8-week old C57BL/6 male mice and performed locomotion recording 6 months post-operatively. Additionally, we performed the same recording after oral administration of the selective cyclooxygenase-2 inhibitor to determine whether alteration of the parameters were associated with joint pain.

Results: OA development, characterized by cartilage degeneration and osteophyte formation, was markedly enhanced in the OA group. There was no significant difference between the sham and OA groups in basic gait parameters, including stance duration, swing duration and gait cycle. However, when we divided the gait cycle into four phases and calculated the joint ranges of motion in each phase, the range of motion of the knee joint during the stepping-in phase and the swing duration were significantly decreased in the OA group. These significant differences between the sham and OA groups were diminished by the oral administration of a selective cyclooxygenase-2 inhibitor to the OA group.

Conclusion: The present method may be useful to evaluate joint pain in experimental mice and contribute to elucidating the molecular mechanisms of pain in the OA knee joint in combination with genetically modified mice.
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http://dx.doi.org/10.1177/2309499018768017DOI Listing
October 2019

Biphasic regulation of chondrocytes by Rela through induction of anti-apoptotic and catabolic target genes.

Nat Commun 2016 11 10;7:13336. Epub 2016 Nov 10.

Department of Sensory &Motor System Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.

In vitro studies have shown that Rela/p65, a key subunit mediating NF-κB signalling, is involved in chondrogenic differentiation, cell survival and catabolic enzyme production. Here, we analyse in vivo functions of Rela in embryonic limbs and adult articular cartilage, and find that Rela protects chondrocytes from apoptosis through induction of anti-apoptotic genes including Pik3r1. During skeletal development, homozygous knockout of Rela leads to impaired growth through enhanced chondrocyte apoptosis, whereas heterozygous knockout of Rela does not alter growth. In articular cartilage, homozygous knockout of Rela at 7 weeks leads to marked acceleration of osteoarthritis through enhanced chondrocyte apoptosis, whereas heterozygous knockout of Rela results in suppression of osteoarthritis development through inhibition of catabolic gene expression. Haploinsufficiency or a low dose of an IKK inhibitor suppresses catabolic gene expression, but does not alter anti-apoptotic gene expression. The biphasic regulation of chondrocytes by Rela contributes to understanding the pathophysiology of osteoarthritis.
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http://dx.doi.org/10.1038/ncomms13336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5109547PMC
November 2016

Regulation of Chondrocyte Survival in Mouse Articular Cartilage by p63.

Arthritis Rheumatol 2017 03;69(3):598-609

University of Tokyo, Tokyo, Japan.

Objective: Transcription factor p63, of the p53 family, regulates cell proliferation, survival, and apoptosis in various cells and tissues. This study was undertaken to examine the expression and roles of p63 transcript variants in the mouse growth plate and articular chondrocytes.

Methods: For in vivo analyses, we generated Cre-mediated TAp63α-transgenic and TAp63γ-transgenic mice. To induce tissue-specific overexpression or deletion in chondrocytes, chondroprogenitor cells, or early limb bud mesenchymal cells, we used Col2a1-Cre, Sox9-Cre, and Prx1-Cre mice, respectively. We analyzed osteoarthritis (OA) development with aging or surgically induced instability in Prx1-Cre;p63 (P-conditional knockout) mice.

Results: Among major variants, TAp63α and TAp63γ are highly expressed in mouse primary costal and articular chondrocytes. The p63 protein was predominantly localized in the hypertrophic zone of the embryonic limb cartilage, and in the middle zone of articular cartilage. No obvious change was observed in skeletal growth of TAp63α-transgenic mice, Sox9-Cre;p63 , or P-conditional knockout mice, while that of TAp63γ-transgenic mice was impaired due to ectopic apoptosis and the resulting decreased number of chondrocytes. Expression of proapoptotic genes including bax, noxa, puma, and fas was increased in TAp63γ-transgenic mouse chondrocytes, and their transcription was probably sustained by p53 in p63-conditional knockout mouse chondrocytes because both proteins were coexpressed in the growth plate. In contrast, p53 was expressed in the superficial zone of articular cartilage, differently from p63. Notably, P-conditional knockout mice showed significant resistance to OA development, with suppression of chondrocyte apoptosis in the aging and surgical models.

Conclusion: We demonstrated regulation of chondrocyte survival in articular cartilage by p63.
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http://dx.doi.org/10.1002/art.39976DOI Listing
March 2017

Transcription factor Hes1 modulates osteoarthritis development in cooperation with calcium/calmodulin-dependent protein kinase 2.

Proc Natl Acad Sci U S A 2015 Mar 2;112(10):3080-5. Epub 2015 Mar 2.

Sensory & Motor System Medicine, Bone and Cartilage Regenerative Medicine,

Notch signaling modulates skeletal formation and pathogenesis of osteoarthritis (OA) through induction of catabolic factors. Here we examined roles of Hes1, a transcription factor and important target of Notch signaling, in these processes. SRY-box containing gene 9 (Sox9)-Cre mice were mated with Hes1(fl/fl) mice to generate tissue-specific deletion of Hes1 from chondroprogenitor cells; this deletion caused no obvious abnormality in the perinatal period. Notably, OA development was suppressed when Hes1 was deleted from articular cartilage after skeletal growth in type II collagen (Col2a1)-Cre(ERT);Hes1(fl/fl) mice. In cultured chondrocytes, Hes1 induced metallopeptidase with thrombospondin type 1 motif, 5 (Adamts5) and matrix metalloproteinase-13 (Mmp13), which are catabolic enzymes that break down cartilage matrix. ChIP-seq and luciferase assays identified Hes1-responsive regions in intronic sites of both genes; the region in the ADAMTS5 gene contained a typical consensus sequence for Hes1 binding, whereas that in the MMP13 gene did not. Additionally, microarray analysis, together with the ChIP-seq, revealed novel Hes1 target genes, including Il6 and Il1rl1, coding a receptor for IL-33. We further identified calcium/calmodulin-dependent protein kinase 2δ (CaMK2δ) as a cofactor of Hes1; CaMK2δ was activated during OA development, formed a protein complex with Hes1, and switched it from a transcriptional repressor to a transcriptional activator to induce cartilage catabolic factors. Therefore, Hes1 cooperated with CaMK2δ to modulate OA pathogenesis through induction of catabolic factors, including Adamts5, Mmp13, Il6, and Il1rl1. Our findings have contributed to further understanding of the molecular pathophysiology of OA, and may provide the basis for development of novel treatments for joint disorders.
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http://dx.doi.org/10.1073/pnas.1419699112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4364241PMC
March 2015

Identification of SCAN domain zinc-finger gene ZNF449 as a novel factor of chondrogenesis.

PLoS One 2014 29;9(12):e115169. Epub 2014 Dec 29.

Sensory & Motor System Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan; Bone and Cartilage Regenerative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

Transcription factors SOX9, SOX5 and SOX6 are indispensable for generation and differentiation of chondrocytes. However, molecular mechanisms to induce the SOX genes are poorly understood. To address this issue, we previously determined the human embryonic enhancer of SOX6 by 5'RACE analysis, and identified the 46-bp core enhancer region (CES6). We initially performed yeast one-hybrid assay for screening other chondrogenic factors using CES6 as bait, and identified a zinc finger protein ZNF449. ZNF449 and Zfp449, a counterpart in mouse, transactivated enhancers or promoters of SOX6, SOX9 and COL2A1. Zfp449 was expressed in mesenchyme-derived tissues including cartilage, calvaria, muscle and tendon, as well as in other tissues including brain, lung and kidney. In limb cartilage of mouse embryo, Zfp449 protein was abundantly located in periarticular chondrocytes, and decreased in accordance with the differentiation. Zfp449 protein was also detected in articular cartilage of an adult mouse. During chondrogenic differentiation of human mesenchymal stem cells, ZNF449 was increased at an early stage, and its overexpression enhanced SOX9 and SOX6 only at the initial stage of the differentiation. We further generated Zfp449 knockout mice to examine the in vivo roles; however, no obvious abnormality was observed in skeletal development or articular cartilage homeostasis. ZNF449 may regulate chondrogenic differentiation from mesenchymal progenitor cells, although the underlying mechanisms are still unknown.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0115169PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4278888PMC
September 2015

Disease-modifying effects of TD-198946 on progressed osteoarthritis in a mouse model.

Ann Rheum Dis 2014 Nov 18;73(11):2062-4. Epub 2014 Aug 18.

Center for Disease Biology and Integrative Medicine, University of Tokyo, Tokyo, Japan Department of Bioengineering, The University of Tokyo, Tokyo, Japan.

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http://dx.doi.org/10.1136/annrheumdis-2014-205672DOI Listing
November 2014

Notch signaling in chondrocytes modulates endochondral ossification and osteoarthritis development.

Proc Natl Acad Sci U S A 2013 Jan 14;110(5):1875-80. Epub 2013 Jan 14.

Sensory and Motor System Medicine, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.

Here we examined the involvement of Notch signaling in the endochondral ossification process, which is crucial for osteoarthritis (OA) development. Intracellular domains of Notch1 and -2 were translocated into the nucleus of chondrocytes with their differentiation in mouse limb cartilage and in mouse and human OA articular cartilage. A tissue-specific inactivation of the Notch transcriptional effector recombination signal binding protein for Ig kappa J (RBPjκ) in chondroprogenitor cells of SRY-box containing gene 9 (Sox9)-Cre;Rbpj(fl/fl) mouse embryos caused an impaired terminal stage of endochondral ossification in the limb cartilage. The RBPjκ inactivation in adult articular cartilage after normal skeletal growth using type II collagen (Col2a1)-Cre(ERT);Rbpj(fl/fl) mice by tamoxifen injection caused resistance to OA development in the knee joint. Notch intracellular domain with the effector RBPjκ stimulated endochondral ossification through induction of the target gene Hes1 in chondrocytes. Among the Notch ligands, Jagged1 was strongly induced during OA development. Finally, intraarticular injection of N-[N-(3,5-diflurophenylacetate)-L-alanyl]-(S)-phenylglycine t-butyl ester (DAPT), a small compound Notch inhibitor, to the mouse knee joint prevented OA development. The RBPjκ-dependent Notch signaling in chondrocytes modulates the terminal stage of endochondral ossification and OA development, representing an extracellular therapeutic target of OA.
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http://dx.doi.org/10.1073/pnas.1207458110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3562777PMC
January 2013

A novel disease-modifying osteoarthritis drug candidate targeting Runx1.

Ann Rheum Dis 2013 May 5;72(5):748-53. Epub 2012 Oct 5.

Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

Objectives: To identify a new disease-modifying osteoarthritis drug (DMOAD) candidate that can effectively repair cartilage by promoting chondrogenic differentiation and halt osteoarthritis (OA) progression by suppressing aberrant hypertrophy.

Methods: We screened 2500 natural and synthetic small compounds for chondrogenic agents via four steps using the Col2GFP-ATDC5 system and identified a small thienoindazole derivative compound, TD-198946, as a novel DMOAD candidate. We tested its efficacy as a DMOAD via intra-articular injections directly into the joint space in a surgically-induced mouse model of OA both at the onset (prevention model) and 4 weeks after (repair model) OA induction. The downstream molecules were screened by microarray analysis. We further investigated the mechanism of the drug action and its molecular target using in vitro and in vivo assays.

Results: TD-198946 strongly induced chondrogenic differentiation without promoting hypertrophy in cell and metatarsal organ cultures. When administered directly into the joint space, TD-198946 successfully prevented and repaired degeneration of the articular cartilage. TD-198946 exerted its effect through the regulation of Runx1 expression, which was downregulated in both mouse and human OA cartilage compared with normal tissue.

Conclusions: Our data suggest that TD-198946 is a novel class of DMOAD candidate, and that targeting Runx1 will provide a promising new approach in the development of disease-modifying drugs against OA.
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http://dx.doi.org/10.1136/annrheumdis-2012-201745DOI Listing
May 2013

Lack of a chondroprotective effect of cyclooxygenase 2 inhibition in a surgically induced model of osteoarthritis in mice.

Arthritis Rheum 2012 Jan;64(1):198-203

Sensory and Motor System Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.

Objective: To investigate the chondroprotective effect of cyclooxygenase 2 (COX-2) inhibition in experimental osteoarthritis (OA).

Methods: The expression of prostaglandin E2 synthetic enzymes was examined by immunostaining of tibial cartilage from mice with surgically induced knee joint instability and from OA patients undergoing total knee arthroplasty. The effect of orally administered celecoxib (10 mg/kg/day and 30 mg/kg/day) or vehicle alone in mice was examined 12 weeks after the induction of OA. To investigate the involvement of COX-1 and COX-2 in OA development, we also created the model in COX-1-homozygous-knockout (Ptgs1-/-) mice and COX-2-homozygous-knockout (Ptgs2-/-) mice. OA severity was assessed using a grading system developed by our group and by the Osteoarthritis Research Society International scoring system.

Results: In mouse and human OA cartilage, the expression of the inducible enzymes COX-2 and microsomal prostaglandin E synthase 1 (mPGES-1) was enhanced, while that of the constitutive enzymes COX-1, cytosolic PGES, and mPGES-2 was suppressed. Daily celecoxib treatment did not prevent cartilage degradation or osteophyte formation during OA development in the mouse model. Furthermore, neither Ptgs1-/- mice nor Ptgs2-/- mice exhibited any significant difference in OA development as compared to wild-type littermates.

Conclusion: The two COX enzymes differ in terms of regulation of their expression during OA development. Nevertheless, experiments using inhibitor and genetic deficiency demonstrated a lack of chondroprotective effect of COX-2 inhibition in the mouse surgical OA model.
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http://dx.doi.org/10.1002/art.33324DOI Listing
January 2012
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