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Hirotaka Kawano

Publications and source records attributed to Hirotaka Kawano.

At least 19 recordsLinked to original sources
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

[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↗
PubMed2005

Androgen receptor gene knockout male mice exhibit impaired cardiac growth and exacerbation of angiotensin II-induced cardiac fibrosis.

Androgen has anabolic effects on cardiac myocytes and has been shown to enhance left ventricular enlargement and function. However, the physiological and patho-physiological roles of androgen in cardiac growth and cardiac stress-induced remodeling remains unclear. We aimed to clarify whether the androgen-nuclear androgen receptor (AR) system contributes to the cardiac growth and angiotensin II (Ang II)-stimulated cardiac remodeling by using systemic AR-null male mice. AR knock-out (ARKO) male mice, at 25 weeks of age, and age-matched wild-type (WT) male mice were treated with or without Ang II stimulation (2.0 mg/kg/day) for 2 weeks. ARKO mice with or without Ang II stimulation showed a significant reduction in the heart-to-body weight ratio compared with those of WT mice. In addition, echocardiographic analysis demonstrated impairments of both the concentric hypertrophic response and left ventricular function in Ang II-stimulated ARKO mice. Western blot analysis of the myocardium revealed that activation of extracellular signal-regulated kinases (ERK) 1/2 and ERK5 by Ang II stimulation were lower in ARKO mice than those of WT mice. Ang II stimulation caused more prominent cardiac fibrosis in ARKO mice than in WT mice with enhanced expression of types I and III collagen and transforming growth factor-beta1 genes and with increased Smad2 activation. These results suggest that, in male mice, the androgen-AR system participates in normal cardiac growth and modulates cardiac adaptive hypertrophy and fibrosis during the process of cardiac remodeling under hypertrophic stress.

Angiotensin II↗
PubMed2005

Androgen receptor null male mice develop late-onset obesity caused by decreased energy expenditure and lipolytic activity but show normal insulin sensitivity with high adiponectin secretion.

Androgen receptor (AR) null male mice (AR(L-/Y)) revealed late-onset obesity, which was confirmed by computed tomography-based body composition analysis. AR(L-/Y) mice were euphagic compared with the wild-type male (AR(X/Y)) controls, but they were also less dynamic and consumed less oxygen. Transcript profiling indicated that AR(L-/Y) mice had lower transcripts for the thermogenetic uncoupling protein 1, which was subsequently found to be ligand-dependently activated by AR. We also found enhanced secretion of adiponectin, which is insulin sensitizing, from adipose tissue and a relatively lower expression of peroxisome proliferator-activated receptor-gamma in white adipose tissue in comparison to AR(X/Y) mice. Both factors might explain why the overall insulin sensitivity of AR(L-/Y) mice remained intact, despite their apparent obesity. The results revealed that AR plays important roles in male metabolism by affecting the energy balance, and it is negative to both adiposity and insulin sensitivity.

Adiponectin↗
PubMed2004

Cyclic GMP-dependent protein kinase II is a molecular switch from proliferation to hypertrophic differentiation of chondrocytes.

The Komeda miniature rat Ishikawa (KMI) is a naturally occurring mutant caused by an autosomal recessive mutation mri, which exhibits longitudinal growth retardation. Here we identified the mri mutation as a deletion in the rat gene encoding cGMP-dependent protein kinase type II (cGKII). KMIs showed an expanded growth plate and impaired bone healing with abnormal accumulation of postmitotic but nonhypertrophic chondrocytes. Ex vivo culture of KMI chondrocytes reproduced the differentiation impairment, which was restored by introducing the adenovirus-mediated cGKII gene. The expression of Sox9, an inhibitory regulator of hypertrophic differentiation, persisted in the nuclei of postmitotic chondrocytes of the KMI growth plate. Transfection experiments in culture systems revealed that cGKII attenuated the Sox9 functions to induce the chondrogenic differentiation and to inhibit the hypertrophic differentiation of chondrocytes. This attenuation of Sox9 was due to the cGKII inhibition of nuclear entry of Sox9. The impaired differentiation of cultured KMI chondrocytes was restored by the silencing of Sox9 through RNA interference. Hence, the present study for the first time shed light on a novel role of cGKII as a molecular switch, coupling the cessation of proliferation and the start of hypertrophic differentiation of chondrocytes through attenuation of Sox9 function.

Animals↗
PubMed2004

SRC-1 is necessary for skeletal responses to sex hormones in both males and females.

UNLABELLED: We created SRC-1(-/-) mice by mating floxed SRC-1 mice with CMV-Cre transgenic mice. The SRC-1(-/-) mice showed high turnover osteopenia under physiological conditions and hardly responded to osteoanabolic actions of exogenous androgen and estrogen in males and females, respectively, after gonadectomies, indicating that SRC-1 is essential for the maintenance of bone mass by sex hormones. INTRODUCTION: Steroid receptor coactivator-1 (SRC-1) is the first identified coactivator of nuclear receptors. This study investigated the role of SRC-1 in skeletal tissues of males and females using the deficient (SRC-1(-/-)) mice. MATERIALS AND METHODS: SRC-1(-/-) mice were generated by mating our original floxed SRC-1 mice with CMV-Cre transgenic mice. Bone metabolism between 24-week-old SRC-1(-/-) and wildtype (WT) littermates under physiological conditions was compared in males and females by radiological, histological, and biochemical analyses. Difference of skeletal responses to steroid hormones was examined by gonadectomies and exogenous administration experiments with the hormones. Statistical analysis was performed by ANOVA determined by posthoc testing using Bonferroni's method. RESULTS AND CONCLUSIONS: Although SRC-1(-/-) mice showed no abnormality in growth or major organs, both males and females showed osteopenia with high bone turnover in the trabecular bones, but not in the cortical bones, compared with WT littermates. Their serum levels of sex hormones were upregulated, suggesting a compensatory reaction for the insensitivity to these hormones. Gonadectomies caused decreases in BMDs of SRC-1(-/-) and WT mice to the same levels; however, replacement with 5 alpha-dihydrotestosterone and 17 beta-estradiol in males and females, respectively, failed to restore the bone loss in SRC-1(-/-), whereas the WT bone volume was increased to the sham-operated levels. In contrast, bone loss by administered prednisolone was similarly seen in SRC-1(-/-) and WT mice. We conclude that SRC-1 is essential for the maintenance of bone mass by sex hormones, but not for the catabolic action of glucocorticoid, under both physiological and pathological conditions.

Animals↗
PubMed2004

Simple curettage without bone grafting for enchondromas of the foot.

BACKGROUND: Simple curettage without bone grafting for enchondromas of the hand and its good clinical results have been reported. Yet, there have been no reports regarding simple curettage without bone grafting for enchondromas of the foot. The purpose of this study is to elucidate the clinical results of this method for enchondromas of the foot. METHODS: We studied eight patients (ten bones) with enchondromas of the foot treated with simple curettage without bone grafting. After making an oval or round fenestration, the enchondroma was curetted. The cortical window of the fenestration was excised in five bones, whereas it was replaced at the fenestration site in the other five bones. RESULTS: The affected toe was immobilized with a tape in two patients. All patients began to walk on the day of surgery or the next day without crutches. Sclerotic changes on the plain radiographs were seen 6.4 weeks (range: 4-10 weeks) postoperatively. The patients returned to their normal daily activity including occupation and sport in 8.6 weeks (range: 0-12 weeks) postoperatively. The radiographic appearance was almost normalized in 8.4 months on average (range: 3-14 months). Function was classified as excellent in all bones according to a modified Tordai classification. CONCLUSION: We conclude that simple curettage without bone grafting can be one of the standard surgical treatments for enchondromas of the foot.

Adult↗
PubMed2004

Brain masculinization requires androgen receptor function.

Testicular testosterone produced during a critical perinatal period is thought to masculinize and defeminize the male brain from the inherent feminization program and induce male-typical behaviors in the adult. These actions of testosterone appear to be exerted not through its androgenic activity, but rather through its conversion by brain aromatase into estrogen, with the consequent activation of estrogen receptor (ER)-mediated signaling. Thus, the role of androgen receptor (AR) in perinatal brain masculinization underlying the expression of male-typical behaviors remains unclear because of the conversion of testosterone into estrogen in the brain. Here, we report a null AR mutation in mice generated by the Cre-loxP system. The AR-null mutation in males (AR(L-/Y)) resulted in the ablation of male-typical sexual and aggressive behaviors, whereas female AR-null homozygote (AR(L-/L-)) mice exhibited normal female sexual behaviors. Treatment with nonaromatizable androgen (5alpha-dihydrotestosterone, DHT) was ineffective in restoring the impaired male sexual behaviors, but it partially rescued impaired male aggressive behaviors in AR(L-/Y) mice. Impaired male-typical behaviors in ERalpha(-/-) mice were restored on DHT treatment. The role of AR function in brain masculinization at a limited perinatal stage was studied in AR(L-/L-) mice. Perinatal DHT treatment of females led to adult females sensitive to both 17beta-estradiol and DHT in the induction of male-typical behaviors. However, this female brain masculinization was abolished by AR inactivation. Our results suggested that perinatal brain masculinization requires AR function and that expression of male-typical behaviors in adults is mediated by both AR-dependent and -independent androgen signaling.

Androgen Receptor Antagonists↗
PubMed2004

Spindle cell lipoma of the knee: a case report.

A rare case of spindle cell lipoma of the knee in a 58-year-old woman is presented. A soft tissue mass on the lateral aspect of the knee, measuring 5 x 6 cm in size, that had been noticed 1 year previously showed slightly lower signal intensities both on T1- and T2-weighted magnetic resonance images than those of subcutaneous adipose tissue. Because pathological findings of the tiny specimen obtained by needle biopsy showed lipogenic tumor and the possibility of well-differentiated liposarcoma could not be ruled out, wide excision was performed. Histopathological examination revealed that the tumor consisted of spindle cells, collagen fibers, and lipocytes. In addition, immunohistochemical study showed positive staining for CD34. From these histological findings, diagnosis of spindle cell lipoma was made. Although expected sites of spindle cell lipoma are the posterior neck, shoulder region, and upper back, it may also arise in the lower extremity. Therefore, when radiological findings suggest lipogenic tumor but are different from those of lipoma, spindle cell lipoma as well as well-differentiated liposarcoma should be considered for differential diagnoses.

Antigens, CD34↗
PubMed2004

Function of androgen receptor in gene regulations.

Most of the androgen actions are considered to be mediated by the androgen receptor (AR) of the target genes. The AR is composed of a fairly large molecule because of the long A/B domains of its N-terminal. However, the independent roles of the AR as well as those of the estrogen receptors largely remained unknown mainly due to the lack of the AR knockout (ARKO) mice line. We have succeeded in generating the ARKO mouse by means of a conditional targeting using the Cre/loxP system. The ARKO males grew healthily although they showed a typical feature of the testicular feminization mutation (Tfm) and the hormonal assay revealed significantly lower serum androgen and higher LH levels in comparison with those of the wild type (WT) males. The serum estrogen levels were, however, comparable between both the ARKO and the WT. Another hallmark of the ARKO males was a state of high bone turnover osteopenia, in which the acceleration in the bone resorption clearly exceeded the bone formation. Male-typical behaviors were disrupted in male ARKO mice. Aiming at a quick differentiation of an androgen-dependent polyQ disease such as Kennedy's disease, the authors also developed the Drosophila fly-eye model in which the wild type and the polyQ-expanded human AR (hAR) was induced in the eyes of Drosophila. When androgen was administered to the flies induced with the polyQ-expanded hAR, their optical nerves were devastated.

Animals↗
PubMed2003

Cystatin 10, a novel chondrocyte-specific protein, may promote the last steps of the chondrocyte differentiation pathway.

This study attempts to characterize cystatin 10 (Cst10), which we recently identified as a novel protein implicated in endochondral ossification. Expression of Cst10 was specific to cartilage, localized in the cytosol of prehypertrophic and hypertrophic chondrocytes of the mouse growth plate. In the mouse chondrogenic cell line ATDC5, Cst10 expression preceded type X collagen expression and increased in synchrony with maturation. When we compared ATDC5 cells transfected with Cst10 cDNA with cells transfected with a mock vector, hypertrophic maturation and mineralization of chondrocytes were promoted by Cst10 gene overexpression in that type X collagen expression was observed earlier, and alizarin red staining was stronger. On the other hand, type II collagen expression and Alcian blue staining, both of which are markers of the early stage of chondrocyte differentiation, were similar in both cells. Overexpression of the Cst10 gene also caused fragmentation of nuclei, the appearance of annexin V, a change in the mitochondrial membrane potential, and activation of caspases. These results strongly suggest that Cst10 may play an important role in the last steps of the chondrocyte differentiation pathway as an inducer of maturation, followed by apoptosis of chondrocytes.

Alcian Blue↗
PubMed2003

Suppressive function of androgen receptor in bone resorption.

As locally converted estrogen from testicular testosterone contributes to apparent androgen activity, the physiological significance of androgen receptor (AR) function in the beneficial effects of androgens on skeletal tissues has remained unclear. We show here that inactivation of AR in mice using a Cre-loxP system-mediated gene-targeting technique caused bone loss in males but not in females. Histomorphometric analyses of 8-week-old male AR knockout (ARKO) mice showed high bone turnover with increased bone resorption that resulted in reduced trabecular and cortical bone mass without affecting bone shape. Bone loss in orchidectomized male ARKO mice was only partially prevented by treatment with aromatizable testosterone. Analysis of primary osteoblasts and osteoclasts from ARKO mice revealed that AR function was required for the suppressive effects of androgens on osteoclastogenesis supporting activity of osteoblasts but not on osteoclasts. Furthermore, expression of the receptor activator of NF-kappaB ligand (RANKL) gene, which encodes a major osteoclastogenesis inducer, was found to be up-regulated in osteoblasts from AR-deficient mice. Our results indicate that AR function is indispensable for male-type bone formation and remodeling.

Androgen-Insensitivity Syndrome↗
PubMed2003

Late onset of obesity in male androgen receptor-deficient (AR KO) mice.

An androgen receptor (AR) null mutant mice line was generated by means of a Cre-lox P system. The male (AR(L-/Y)) (KO) mice exhibited typical features of testicular feminization mutant (Tfm) disease in external reproductive organs with growth retardation. The growth curve of the male AR KO mice was similar to that of the wild-type female littermates until the 10th week of age, but thereafter a drastic increase in the growth was observed with development of obesity. Clear increase in the wet weights of white adipose tissues, but not of brown adipose tissue, was found in the 30-week-old male AR KO mice. However, no significant alteration in serum lipid parameters and food intake was observed. Thus, the present results suggest that AR may serve as a negative regulator of adipose development in adult males.

Adipocytes↗
PubMed2003

Chondromodulin I is a bone remodeling factor.

Chondromodulin I (ChM-I) was supposed from its limited expression in cartilage and its functions in cultured chondrocytes as a major regulator in cartilage development. Here, we generated mice deficient in ChM-I by targeted disruption of the ChM-I gene. No overt abnormality was detected in endochondral bone formation during embryogenesis and cartilage development during growth stages of ChM-I(-/-) mice. However, a significant increase in bone mineral density with lowered bone resorption with respect to formation was unexpectedly found in adult ChM-I(-/-) mice. Thus, the present study established that ChM-I is a bone remodeling factor.

Alleles↗
PubMed2003

[Bone metabolism in androgen receptor-deficient mice].

Although the physiological significance of estrogen receptor function on skeletal tissues has been established, that of androgen receptor (AR) function has remained unclear. We show here that inactivation of AR in mice using a Cre-loxP system-mediated gene targeting technique caused bone loss in males, but not in females, which indicated that AR function is indispensable for male-type bone formation and remodeling.

English Abstract↗
PubMed2002

Primary leiomyosarcoma of the femur.

Leiomyosarcoma usually arises in the uterus, gastrointestinal tract, retroperitoneum, or soft tissue. Primary leiomyosarcoma of bone is rare. We encountered two patients with primary leiomyosarcoma of the femur; one was a 24-year-old woman and the other, a 41-year-old woman. Bone destruction observed on plain radiographs was minimal in both patients. Magnetic resonance imaging (MRI) showed low signal intensity on T1-weighted images and high signal intensity on T2-weighted images, with these areas being much larger than the findings to be expected from the plain radiographs. Histological examination revealed spindle-cell sarcoma, with an interlacing pattern, acidophilic cytoplasm and blunt-ended or "cigar-shaped" nuclei, in both patients. In both patients, immunohistochemical examination showed positive staining for vimentin, desmin, and alpha-smooth muscle actin. Extensive examination of the gastrointestinal tract and uterus revealed no primary lesion. Therefore, the leiomyosarcoma in the femur was considered to be primary rather than metastatic. Histological examination, including immunohistochemistry, and the exclusion of an extraskeletal primary lesion, is necessary in diagnosing primary leiomyosarcoma of bone.

Adult↗
PubMed2002

Intraosseous lipoma: a clinical study of 12 patients.

We studied 12 patients (13 bones) with intraosseous lipoma to elucidate the clinical features of this disease. The patients ranged in age from 14 to 54 years. Eleven patients were men and 1 was a woman. The involved bones were the calcaneus in 6 patients (7 bones), humerus in 3, ischium in 2, and sacrum in 1. Three bones were in Milgram's stage I, 8 were in stage II, and 2 were in stage III. On plain radiographs, all bones showed a well-circumscribed radiolucent area. Nine bones showed calcification or ossification. Computed tomography or magnetic resonance imaging showed low density or high signal intensity, respectively, identical to the findings in normal adipose tissue. The tumor was curetted in 3 patients (3 bones), in whom local recurrence was not seen thereafter. In the remaining 9 patients (10 bones), we observed the natural course; in 1 of these patients, incisional biopsy was performed. During the follow-up period, only 1 patient showed slight enlargement of the lesion, while the findings in the others remained unchanged. Three patients had pain, which disappeared after the surgery or during the course of the observation. Partly because intraosseous lipoma tends to undergo spontaneous involution, and partly because diagnosis is easy from the radiological findings, surgery does not seem to be necessary in most patients.

Adolescent↗