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Hiroshi Kawaguchi

Publications and source records attributed to Hiroshi Kawaguchi.

At least 19 recordsLinked to original sources
PubMed2026

Temporal mismatch in allogeneic iPSC therapies: biological risks and implications for clinical translation.

INTRODUCTION: The clinical translation of pluripotent stem cell-derived therapies has entered a new phase following conditional approval of first-in-class allogeneic induced pluripotent stem cell (iPSC)-derived products in Japan. These approvals highlight both the therapeutic promise of iPSC technologies and regulatory challenges associated with evaluating complex cell-based interventions. AREAS COVERED: This report examines the evidentiary basis supporting recent approvals and reviews key biological characteristics of allogeneic iPSC-derived therapies, including pluripotency-associated instability, immunological constraints, and manufacturing-related genomic variability. Drawing on recent clinical studies and relevant experimental literature, we analyze how these multilayered risks evolve over extended time horizons and assess their implications for the interpretation of early-phase clinical data and current regulatory frameworks. EXPERT OPINION: We argue that the central challenge extends beyond limited clinical evidence to a fundamental mismatch between the temporal dynamics of biological risk and the duration of conventional clinical evaluation. As a result, early clinical observations may systematically underestimate long-term risks. Conditional approval pathways should therefore incorporate safeguards aligned with this temporal uncertainty, including long-term follow-up, rigorous post-approval evaluation, and enhanced transparency in biological and manufacturing data. Aligning regulatory design with intrinsic properties of pluripotent stem cell-derived therapies will be essential for ensuring safe and responsible clinical translation.

Humans↗
PubMed2007

Local application of recombinant human fibroblast growth factor-2 on bone repair: a dose-escalation prospective trial on patients with osteotomy.

Based on preclinical evidence in animal models, the present study examined the clinical efficacy and safety of recombinant human fibroblast growth factor-2 (rhFGF-2) to accelerate bone repair in a dose-escalation prospective trial. One of three dosages (200, 400 or 800 microg) of rhFGF-2 in a biodegradable gelatin hydrogel was injected during surgery into the osteotomy site of 59 knee osteoarthritis patients undergoing high tibial osteotomy, and 57 of them were monitored for 16 weeks. The rhFGF-2 dose dependently increased the percentage of patients with radiographic bone union, and decreased the average time needed for such union. The percentages of patients with an absence of pain and full-weight bearing were also greater in the higher dosage groups than in the low dosage group, especially in the clinically critical periods 6, 8, and 10 weeks. Neither blood chemistries nor clinical adverse events were associated with the rhFGF-2 dosages. We therefore conclude that the rhFGF-2 in gelatin hydrogel dose dependently accelerated radiographic bone union of a surgical osteotomy with a safety profile at least at the dosages used, suggesting the clinical efficacy of this agent for bone repair.

Adult↗
PubMed2006

Tailor-made tricalcium phosphate bone implant directly fabricated by a three-dimensional ink-jet printer.

Rapid prototyping (RP) is a molding technique that builds a three-dimensional (3D) model from computer-aided design (CAD) data. We fabricated new tailor-made bone implants (TIs) from alpha-tricalcium phosphate powder using an RP ink-jet printer based on computed tomography (CT) data, and evaluated their safety and efficacy. CT data of the skulls of seven beagle dogs were obtained and converted to CAD data, and bone defects were virtually made in the skull bilaterally. TIs were designed to fit the defects and were fabricated using the 3D ink-jet printer with six horizontal cylindrical holes running through the implants, designed for possible facilitation of vascular invasion and bone regeneration. As a control, hydroxyapatite implants (HIs) were cut manually from porous hydroxyapatite blocks. Then, craniectomy was performed to create real skull defects, and TIs and HIs were implanted. After implantation, CT was performed regularly, and the animals were euthanized at 24 weeks. No major side effects were observed. CT analysis showed narrowing of the cylindrical holes; bony bridging between the implants and the temporal bone was observed only for TIs. Histological analysis revealed substantial new bone formation inside the cylindrical holes in the TIs, while mainly connective tissues invaded the porous structures in HIs. Bone marrow was observed only in TIs. Osteoclasts were seen to resorb regenerated bone from inside the cylindrical holes and to invade and probably resorb the TIs. These data suggest that TIs are a safe and effective bone substitute, possessing osteoconductivity comparable with that of HIs.

Animals↗
PubMed2006

Erk pathways negatively regulate matrix mineralization.

Skeletal mineralization is an important step regulating the mechanical properties of the calcified tissues, but molecular events underlying mineralization still remain elusive. We examined the role of extracellular signal-regulated kinase (Erk) pathways in matrix mineralization of osteogenic cells both in vitro and in vivo. Matrix mineralization by preosteocytic MLO-A5 cells and osteoblastic MC3T3-E1 cells was increased by either PD98059 Mek inhibitor treatment or adenovirus vector-mediated dominant negative Ras (Ras(DN)) expression and was suppressed by Erk activation by platelet-derived growth factor (PDGF) treatment or constitutively active Mek1 (Mek(CA)) expression. Administration of adenovirus vectors carrying Ras(DN) gene onto the calvaria of 1-day-old mice increased the mineralization of the tissues, while that of the Mek(CA) adenovirus suppressed it. These results suggest that the Erk pathway is a negative regulator of the matrix mineralization both in vitro and in vivo.

Actins↗
PubMed2006

Regulation of bone formation by adiponectin through autocrine/paracrine and endocrine pathways.

Since interaction between bone and lipid metabolism has been suggested, this study investigated the regulation of bone metabolism by adiponectin, a representative adipokine, by analyzing deficient and overexpressing transgenic mice. We initially confirmed that adiponectin and its receptors were expressed in osteoblastic and osteoclastic cells, indicating that adiponectin can act on bone not only through an endocrine pathway as a hormone secreted from fat tissue, but also through an autocrine/paracrine pathway. There was no abnormality in bone mass or turnover of adiponectin-deficient (Ad-/-) mice, possibly due to an equivalent balance of the two pathways. In the culture of bone marrow cells from the Ad-/- mice, osteogenesis was decreased compared to the wild-type (WT) cell culture, indicating a positive effect of endogenous adiponectin through the autocrine/paracrine pathway. To examine the endocrine action of adiponectin, we analyzed transgenic mice overexpressing adiponectin in the liver, and found no abnormality in the bone. Addition of recombinant adiponectin in cultured osteoprogenitor cells suppressed osteogenesis, suggesting that the direct action of circulating adiponectin was negative for bone formation. In the presence of insulin, however, this suppression was blunted, and adiponectin enhanced the insulin-induced phosphorylations of the main downstream molecule insulin receptor substrate-1 and Akt. These lines of results suggest three distinct adiponectin actions on bone formation: a positive action through the autocrine/paracrine pathway by locally produced adiponectin, a negative action through the direct pathway by circulating adiponectin, and a positive action through the indirect pathway by circulating adiponectin via enhancement of the insulin signaling.

Adiponectin↗
PubMed2006

Neurologic level diagnosis of cervical stenotic myelopathy.

STUDY DESIGN: A cross-sectional analysis. OBJECTIVE: To elucidate the accuracy of neurologic level diagnosis of cervical stenotic myelopathy. SUMMARY OF BACKGROUND DATA: Neurologic level diagnosis in cervical myelopathy has not been well established. METHODS: A total of 106 patients with cervical stenotic myelopathy, with a single-level intramedullary high-intensity area confirmed on both preoperative and postoperative T2-weighted magnetic resonance imaging (MRI), were included in this study. We performed a level diagnosis on the basis of neurologic signs (the uppermost muscle with weakness, diminished or exaggerated deep tendon reflex, the uppermost level of sensory disturbance of the upper extremities) and compared it with a level diagnosis made by T2-weighted MRI. The sensitivity, specificity, and accuracy of neurologic signs on our index corresponding to each intervertebral level were calculated. RESULTS: The averages of sensitivity, specificity, and accuracy were 42%, 80%, and 70%, respectively, in the uppermost muscle with weakness, 66%, 89%, and 83% in deep tendon reflex, and 74%, 91%, and 87% in the sensory disturbance area. The positive and negative predictive values were 40% and 91%, respectively, in the uppermost muscle with weakness, 66% and 89% in deep tendon reflex, and 74% and 91% in the sensory disturbance area. Accuracy of a diagnosis based on muscle weakness was less high, the reason being that in many patients, the uppermost muscle with weakness was extensor digiti communis or the intrinsic muscles of the hands, and this led to a lower sensitivity. CONCLUSIONS: The average accuracy of neurologic level diagnosis based on the index we proposed was > or =70%. The level diagnosis by a sensory disturbance area showed the highest accuracy (87%).

Adult↗
PubMed2006

Carminerin contributes to chondrocyte calcification during endochondral ossification.

Endochondral ossification is an essential process not only for physiological skeletal development and growth, but also for pathological disorders. We recently identified a novel cartilage-specific molecule, carminerin (also known as cystatin 10 and encoded by Cst10), which is upregulated in synchrony with cartilage maturation and stimulates the later differentiation of cultured chondrocytes. Although carminerin-deficient (Cst10-/-) mice developed and grew normally, they had a microscopic decrease in the calcification of hypertrophic chondrocytes at the growth plate. When we created experimental models of pathological endochondral ossification, we observed suppression of chondrocyte calcification during formation of osteoarthritic osteophytes, age-related ectopic ossification and healing of bone fractures in Cst10-/- mice. Cultured Cst10-/- chondrocytes showed a reduction in calcification with activation of an SRY site in the promoter of the gene encoding nucleotide pyrophosphatase phosphodiesterase 1 (NPP1, encoded by Enpp1). Functional NPP1 is required for carminerin deficiency to suppress the pathological endochondral ossifications listed above. Carminerin is the first cartilage-specific protein that contributes to chondrocyte calcification during endochondral ossification under physiological and pathological conditions through the transcriptional inhibition of NPP1.

Animals↗
PubMed2006

A large-scale genetic association study of ossification of the posterior longitudinal ligament of the spine.

Research to date has identified several genes that are implicated in the etiology of ossification of the posterior longitudinal ligament of the spine (OPLL); however, their pathogenetic relevance remains obscure. The aim of this study is to identify susceptibility genes for OPLL through a large-scale case-control association study and to re-examine previously reported associations. A total of 109 single nucleotide polymorphisms (SNPs) in 35 candidate genes were genotyped for 711 sporadic OPLL patients and 896 controls. The differences in allelic and genotypic distribution between patients and controls were assessed using the chi (2) test with Bonferroni's correction. We also analyzed the association by separating patients into subgroups according to sex, age and the number of ossified vertebrae. The nominal P values fell below 0.05 for five SNPs in three genes. An intronic SNP in the TGF3 gene (P=0.00040) showed the most significant association. Previously reported associations of COL11A2, NPPS and TGFB1 with OPLL could not be reproduced. Further, no significant associations were detected in stratified analyses based on sex, age or the number of ossified vertebrae. TGFB3 warrants further investigation because it is located within a genomic region that has been positively linked with OPLL.

Adolescent↗
PubMed2006

Contribution of runt-related transcription factor 2 to the pathogenesis of osteoarthritis in mice after induction of knee joint instability.

OBJECTIVE: By producing instability in mouse knee joints, we attempted to determine the involvement of runt-related transcription factor 2 (RUNX-2), which is required for chondrocyte hypertrophy, in the development of osteoarthritis (OA). METHODS: An experimental mouse OA model was created by surgical transection of the medial collateral ligament and resection of the medial meniscus of the knee joints of heterozygous RUNX-2-deficient (Runx2+/-) mice and wild-type littermates. Cartilage destruction and osteophyte formation in the medial tibial cartilage were compared by histologic and radiographic analyses. Localization of type X collagen and matrix metalloproteinase 13 (MMP-13) was examined by immunohistochemistry. Localization of RUNX-2 was determined by X-Gal staining in heterozygous RUNX-2-deficient mice with the lacZ gene insertion at the Runx2-deletion site (Runx2+/lacZ). Messenger RNA levels of type X collagen, MMP-13, and RUNX-2 were examined by real-time reverse transcriptase-polymerase chain reaction analysis. RESULTS: RUNX-2 was induced in the articular cartilage of wild-type mice at the early stage of OA, almost simultaneously with type X collagen but earlier than MMP-13. Runx2+/- and Runx2+/lacZ mice showed normal skeletal development and articular cartilage; however, after induction of knee joint instability, they exhibited decreased cartilage destruction and osteophyte formation, along with reduced type X collagen and MMP-13 expression, as compared with wild-type mice. CONCLUSION: RUNX-2 contributes to the pathogenesis of OA through chondrocyte hypertrophy and matrix breakdown after the induction of joint instability.

Animals↗
PubMed2006

Cartilage tissue engineering using human auricular chondrocytes embedded in different hydrogel materials.

To seek a suitable scaffold for cartilage tissue engineering, we compared various hydrogel materials originating from animals, plants, or synthetic peptides. Human auricular chondrocytes were embedded in atelopeptide collagen, alginate, or PuraMatrix, all of which are or will soon be clinically available. The chondrocytes in the atelopeptide collagen proliferated well, while the others showed no proliferation. A high-cell density culture within each hydrogel enhanced the expression of collagen type II mRNA, when compared with that without hydrogel. By stimulation with insulin and BMP-2, collagen type II and glycosaminoglycan were significantly accumulated within all hydrogels. Chondrocytes in the atelopeptide collagen showed high expression of beta1 integrin, seemingly promoting cell-matrix signaling. The N-cadherin expression was inhibited in the alginate, implying that decrease in cell-to-cell contacts may maintain chondrocyte activity. The matrix synthesis in PuraMatrix was less than that in others, while its Young's modulus was the lowest, suggesting a weakness in gelling ability and storage of cells and matrices. Considering biological effects and clinical availability, atelopeptide collagen may be accessible for clinical use. However, because synthetic peptides can control the risk of disease transmission and immunoreactivities, some improvement in gelling ability would provide a more useful hydrogel for ideal cartilage regeneration.

Atrial Appendage↗
PubMed2006

Decreased activities of daily living and associations with bone loss among aged residents in a rural Japanese community: the Miyama Study.

The present study aimed to clarify frequencies of decreased activities of daily living (ADL) and associations with rate of bone loss among inhabitants more than 60 years old in Miyama, a rural community in Japan. A cohort of 1543 inhabitants aged 40-79 years was established according to Miyama resident registrations in 1989. Men (n = 50) and women (n = 50) from each of two age strata between 60 and 79 years (N = 200) were selected from this cohort, and bone mineral density (BMD) of the lumbar spine and proximal femur was measured using dual-energy X-ray absorptiometry in 1990 (initial survey) and again in 1993, 1997, and 2000. Difficulties involving ADL were surveyed at every follow-up study. Of the 200 initial participants, 124 (57 men, 67 women; 62.0%) completed all BMD measurements and answered all items about ADL in the follow-up survey. The following items were investigated as a general indication of changes to ADL: reaching objects on a high shelf or cupboard (reaching); washing and drying the body (washing body); washing hair over a washbasin (washing hair); sitting for 1 h on a hard chair (sitting); raising the torso from a lying position in bed (raising); standing continuously for 30 min (standing); taking socks on and off the feet (taking socks); bending down from a seated position and picking up a small object at the side of the chair (bending); lifting heavy objects (lifting); and running 100 m without stopping (running). Among ADL items, the most frequent difficulties in men involved running (50.0%), followed by raising (30.6%), standing (27.1%), sitting (24.7%), and reaching (16.5%). In women, difficulties involved running (67.0%), followed by lifting (36.3%), standing (33.1%), reaching (30.8%), and sitting (23.6%). To evaluate relationships between decreased ADL and changes in BMD, annual rates of change for BMD at the lumbar spine and femoral neck were compared to changes for each ADL item (2 grade decrease; 1 grade decrease; or no change). Analysis of covariance (ANCOVA) was then performed on decreased ADL and annual bone changes after adjustment for age, concomitant disease (previous fractures, gastrectomy, diabetes mellitus, and renal dialysis at initial survey). In men, annual rates of change in BMD at the femoral neck over 10 years were significantly correlated with decreased abilities in bending (P = 0.046; R2 = 0.10). In women, annual rates of change in BMD at the lumbar spine over 10 years were significantly correlated with decreased abilities in reaching (P = 0.007; R2 = 0.25), and lifting (P = 0.014, R2 = 0.27), and those at the femoral neck were significantly correlated with decreased abilities in lifting (P = 0.001, R2 = 0.33).

Activities of Daily Living↗
PubMed2006

Risk factors for knee osteoarthritis in Japanese men: a case-control study.

Risk of knee osteoarthritis (OA) was assessed in a population-based case-control study of Japanese men. The study covered three health districts in Wakayama and Osaka prefectures, Japan. Subjects were male individuals >or=45 years old diagnosed radiographically with knee OA, and who did not display any established causes of secondary OA. Controls selected randomly from the general population were individually matched to cases for age, sex, and residential district. Subjects were interviewed using structured questionnaires to determine medical history, physical activity, socio-economic factors, and occupation. Interviews were obtained from 37 cases and 37 controls. In univariate analysis, heaviest weight in the past and physical work such as factory, construction, agricultural, or fishery work as the principal occupation significantly raised the risk of male knee OA (P<0.05). Odds ratios (OR) were determined using conditional logistic regression analysis mutually adjusted for potential risk factors using the results of univariate analysis. Heaviest weight in the past (OR 6.01, 95% confidence interval (CI) 1.18-30.5, P<0.05), past knee injury (OR 6.25, 95% CI 1.13-34.5, P<0.05), and physical work as the principal occupation (OR 6.20, 95% CI 1.40-27.5, P<0.05) represented independent factors associated with knee OA after controlling for other risk factors. Physical work is associated with knee OA, demonstrating the influence of working activity on the development of OA. The present study suggests that risk factors for knee OA in men resemble those in women.

Aged↗
PubMed2006

Molecular backgrounds of age-related osteoporosis from mouse genetics approaches.

Backgrounds underlying age-related bone loss can be classified into two categories: systemic abnormality and osteoblast dysfunction. The former includes insufficiency of vitamin D or estrogen, causing a negative balance of calcium metabolism. We propose the contribution of an aging-suppressing gene, klotho, as a novel systemic factor, as a mouse deficient in the klotho gene exhibits multiple aging phenotypes including osteopenia with a low bone turnover. As a factor intrinsic to osteoblasts, we investigated the role of PPARgamma, a key regulator of adipocyte differentiation, based on the facts that osteoblasts and adipocytes share a common progenitor. Heterozygous PPARgamma-deficient mice exhibited high bone mass by stimulating osteoblastogenesis from bone marrow progenitors, and this effect became prominent with aging, indicating involvement of PPARgamma-dependent bone formation in the pathophysiology of age-related bone loss. The local environment of osteoblasts is mainly controlled by cytokines/growth factors, among which insulin-like growth factor-I (IGF-I) is the most possible candidate whose production and activity are decreased with aging. Bone phenotypes of deficient mice of insulin receptor substrates (IRS-1 and IRS-2), essential molecules for intracellular signaling of IGF-I, revealed that IRS-1 is essential to maintain bone turnover by up-regulating anabolic and catabolic functions of osteoblasts, while IRS-2 is needed to keep the predominance of the anabolic function over the catabolic function. A next task ahead of us will be to elucidate the network system of these factors underlying age-related osteoporosis.

Animals↗
PubMed2006

2006 Frank Stinchfield Award: grafting of biocompatible polymer for longevity of artificial hip joints.

Aseptic loosening induced by wear particles from the polyethylene liner is likely the most common cause of long-term total hip arthroplasty failure. We developed a novel hip polyethylene liner with the surface graft of a biocompatible phospholipid polymer, 2-methacryloyloxyethyl phosphorylcholine (MPC), and previously reported the grafting decreased the short-term production of wear particles and the subsequent bone resorptive responses. For clinical application, we investigated the stability of the 2-methacryloyloxyethyl phosphorylcholine grafting during sterilization and the wear resistance of the sterilized liner during longer loading comparable to clinical usage. Radiographic spectroscopy confirmed the stability of the 2-methacryloyloxyethyl phosphorylcholine polymer on the liner surface after the gamma irradiation. We used a hip wear simulator up to 1 x 10(7) cycles to test sterilized cross-linked polyethylene liners with and without 2-methacryloyloxyethyl phosphorylcholine grafting. The 2-methacryloyloxyethyl phosphorylcholine grafting markedly decreased the friction, the production of wear particles, and the wear of the liner surface. These data suggest a marked improvement in the wear resistance of the polyethylene liner by the 2-methacryloyloxyethyl phosphorylcholine grafting for clinically relevant periods after sterilization, indicating 2-methacryloyloxyethyl phosphorylcholine grafting is a promising technology for extending longevity of artificial hips.

Gamma Rays↗
PubMed2006

Immunodominant epitope in the C-terminus of a variable major protein in Borrelia duttonii, an agent of tick-borne relapsing fever.

Borrelia duttonii strain Ly was isolated from a child with tick-borne relapsing fever in Tanzania. B. duttonii produces variable major proteins (Vmps), which undergo antigenic variation. We previously reported transcription of the vmpP gene, which is one of the Vmp genes in strain Ly, detected in vitro cultivation. In the current study, we purified the recombinant non-lipidated VmpP protein by affinity chromatography and produced VmpP polyclonal antibodies. Antigenicity of VmpP was examined by Western immunoblot analysis and peptide-based enzyme-linked immunosorbent assays. Antigenic epitopes were shown to comprise five regions interspersed within the VmpP primary amino acid sequence. Synthetic peptides spanning residues of three of five regions, 232-237 (LASIVD), 280-285 (AGGIAL), and 350-355 (KAADQQ), reacted strongly with the VmpP-specific antibody and these residues were identified as epitopes. In particular, the C-terminal domain (KAADQQ) of this protein was immunoreactive. Further research based on our results will promote the development of a recombinant vaccine for B. duttonii infection.

Amino Acid Sequence↗
PubMed2006

[Androgen function on skeletal tissues: analysis of androgen receptor-deficient mice].

Although sex hormones had been thought to be essential for normal skeletal development and maintenance of bone mass, the physiological role of androgen receptor (AR) in skeletal tissues was not well established. To reveal physiological function of AR on skeletal tissues, we generated AR deficient mice (AR KO) by means of the Cre-loxP system that was used to avoid the problem of male infertility and analyzed their phenotype in skeletal tissues. It was indicated that AR contributes to maintain bone mass in male, but not in female in mice. However, recent studies suggested the contribution of sex hormones to maintain bone mass is different not only between sexes but among species due to the difference of aromatase activity.

Androgens↗