Published papers

Objective. This retrospective study was designed to evaluate the outcomes of four different surgical reconstructions for extensor tendon ruptures in ulnar three fingers in 48 patients with rheumatoid arthritis. Methods. The following four techniques were performed; palmaris longus tendon grafting (PL group; n = 9), extensor indicis proprius (EIP) tendon transfers (EIP group; n = 8), end-to-side transfers with tension-reduced early mobilization (End-to-side group; n = 16), and a combination of end-to-side and EIP transfers (Combination group; n = 15). Loss of extension was evaluated to determine the mean postoperative range of motion of the metacarpophalangeal (MP) joint and clinical outcomes were categorized using modified Geldmacher criteria. Results. Combination group demonstrated the best mean MP joint extension (- 3°), followed by End-to-side group (- 12°), EIP group (- 16°), and PL group (- 21°). Combination group yielded the best clinical outcomes with all cases showing good results. Conclusions. The combination of end-to-side and EIP transfer was an effective surgical reconstruction procedure for triple fingers extension loss.

The number of osteoporosis patients is increasing not only in women but in men. Male osteoporosis occurs due to aging or androgen depletion therapies, leading to fractures. However, molecular mechanisms underlying male osteoporosis remain unidentified. Here, we show that hypoxia inducible factor 1 alpha (Hif1α) is required for development of testosterone deficiency-induced male osteoporosis. We found that in mice Hif1α protein accumulates in osteoclasts following orchidectomy (ORX) in vivo. In vitro, Hif1α protein accumulated in osteoclasts cultured in hypoxic conditions, but Hif1α protein rather than mRNA levels were suppressed by testosterone treatment, even in hypoxia. Administration of a Hif1α inhibitor to ORX mice abrogated testosterone deficiency-induced osteoclast activation and bone loss but did not alter osteoclast activities or bone phenotypes in sham-operated, testosterone-sufficient animals. We conclude that Hif1α protein accumulation due to testosterone-deficiency promotes development of male osteoporosis. Thus Hif1α protein could be targeted to inhibit pathologically-activated osteoclasts under testosterone-deficient conditions to treat male osteoporosis patients.

Study Design. Retrospective study. Objective. To examine the reliabilities of sagittal spino-pelvic alignment measurements using whole spine-pelvic and local pelvic radiographs and to determine whether spinal deformity affects these reliabilities. Summary of Background Data. Sagittal spino-pelvic alignment is important in adult spinal deformity patients (ASD). Spino-pelvic parameters are closely related to health-related quality of life and indispensable for surgical planning. However, few studies have focused on the reliability of these measurements. Methods. Three spino-pelvic parameters, pelvic incidence (PI), pelvic tilt (PT), and sacral slope (SS) were measured in 2 patient groups: 33 adult scoliosis (AS) and 33 nondeformity (ND) patients, using whole spine-pelvic lateral radiographs (whole spine radiographs) and local pelvic lateral radiographs (local pelvic radiographs), by 5 experienced spine surgeons. Intra- and interobserver reliabilities for each procedure were evaluated by intraclass correlation coefficients (ICC). The interobserver reliability differences between the 2 procedures were statistically evaluated. The difference between the largest and smallest measurements among the 5 observers was also evaluated in the AS and ND groups. Results. Measurement of the 3 parameters using whole spine or local pelvic radiographs showed good to excellent intraobserver reliability (range of ICC: 0.820-0.935). The interobserver reliabilities of PI and PT from local pelvic radiographs were significantly higher than those from whole spine radiographs (P

Study Design. This investigation consisted of a cross-sectional study and a retrospective multicenter case series. Objective. This investigation sought to identify the ideal lumbar lordosis (LL) angle for restoring an optimal pelvic tilt (PT) in patients with adult spinal deformity (ASD). Summary of Background Data. To achieve successful corrective fusion in ASD patients with sagittal imbalance, it is essential to correct the sagittal spinal alignment and obtain a suitable pelvic inclination. We determined the LL angle that would restore the optimal PT following ASD surgery. Methods. The cross-sectional study included 184 elderly volunteers (mean age 64 years) with an Oswestry Disability Index score less than 20%. The relationship between PT or LL and the pelvic incidence (PI) in normal individuals was investigated. The second study included 116 ASD patients (mean age 66 years) who underwent thoracolumbar corrective fusion at 1 of 4 spine centers. The postoperative PT values were calculated using the parameters measured. On the basis of these studies, an ideal LL angle was determined. Results. In the cross-sectional study, the linear regression equation for the optimal PT as a function of PI was "optimal PT=0.47×PI-7.5." In the second study, the postoperative PT was determined as a function of PI and corrected LL, using the equation "postoperative PT=0.7×PI-0.5×corrected LL+8.1." The target LL angle was determined by mathematically equalizing the PTs of these 2 equations: "target LL=0.45×PI+31.8." Conclusion. The ideal LL angle can be determined using the equation "LL=0.45×PI+31.8," which can be used as a reference during surgical planning in ASD cases.

Murine- and human-induced pluripotent stem cell-derived neural stem/progenitor cells (iPSC-NS/PCs) promote functional recovery following transplantation into the injured spinal cord in rodents and primates. Although remyelination of spared demyelinated axons is a critical mechanism in the regeneration of the injured spinal cord, human iPSC-NS/PCs predominantly differentiate into neurons both in vitro and in vivo. We therefore took advantage of our recently developed protocol to obtain human-induced pluripotent stem cell-derived oligodendrocyte precursor cell-enriched neural stem/progenitor cells and report the benefits of transplanting these cells in a spinal cord injury (SCI) model. We describe how this approach contributes to the robust remyelination of demyelinated axons and facilitates functional recovery after SCI.

Previous studies have demonstrated that transplantation of neural stem/progenitor cells (NS/PCs) into the lesioned spinal cord can promote functional recovery following incomplete spinal cord injury (SCI) in animal models. However, this strategy is insufficient following complete SCI because of the gap at the lesion epicenter. To obtain functional recovery in a mouse model of complete SCI, this study uses a novel collagen-based microfiber as a scaffold for engrafted NS/PCs. We hypothesized that the NS/PC-microfiber combination would facilitate lesion closure as well as transplant survival in the transected spinal cord. NS/PCs were seeded inside the novel microfibers, where they maintained their capacity to differentiate and proliferate. After transplantation, the stumps of the transected spinal cord were successfully bridged by the NS/PC-laden microfibers. Moreover, the transplanted cells migrated into the host spinal cord and differentiated into three neural lineages (astrocytes, neurons, and oligodendrocytes). However, the NS/PC-laden scaffold could not achieve a neural connection between the rostral end of the injury and the intact caudal area of the spinal cord, nor could it achieve recovery of motor function. To obtain optimal functional recovery, a microfiber design with a modified composition may be useful. Furthermore, combinatorial therapy with rehabilitation and/or medications should also be considered for practical success of biomaterial/cell transplantation-based approaches to regenerative medicine.

Idiopathic scoliosis (IS) is a common paediatric musculoskeletal disease that displays a strong female bias. By performing a genome-wide association study (GWAS) of 3,102 individuals, we identify significant associations with 20p11.22 SNPs for females (P=6.89 × 10 -9) but not males (P=0.71). This association with IS is also found in independent female cohorts from the United States of America and Japan (overall P=2.15 × 10 -10, OR=1.30 (rs6137473)). Unexpectedly, the 20p11.22 IS risk alleles were previously associated with protection from early-onset alopecia, another sexually dimorphic condition. The 174-kb associated locus is distal to PAX1, which encodes paired box 1, a transcription factor involved in spine development. We identify a sequence in the associated locus with enhancer activity in zebrafish somitic muscle and spinal cord, an activity that is abolished by IS-associated SNPs. We thus identify a sexually dimorphic IS susceptibility locus, and propose the first functionally defined candidate mutations in an enhancer that may regulate expression in specific spinal cells.

Background: In 2007, the Japanese orthopaedic association back pain evaluation questionnaire (JOABPEQ) was established to overcome the limitations of the original JOA scoring system developed in 1986. Although this new self-administered questionnaire is a more accurate outcome measure for evaluating patients with low back pain, physicians were unable to as certain the exact status of a patient at a single time point because of a lack of reference values. This study aimed to establish the reference values of JOABPEQ in different age and gender groups using data obtained from healthy volunteers. Methods: This study was conducted in 21 university hospitals and affiliated hospitals from October 2012 to July 2013. The JOABPEQ includes 25 questions that yield five domains to evaluate individuals with low back pain from five different perspectives. A total of 1,456 healthy volunteers (719 men, 737 women; age range, 20–89 years) answered the questionnaire. The differences in scores according to age and gender were examined by non-parametric tests. Results: The JOABPEQ scores significantly decreased with age in the domains of lumbar spine dysfunction, gait disturbance, and social life dysfunction. In these three domains, the median scores approached the 100 possible points in individuals aged 20–70 for both genders. However, the median scores for lumbar spine dysfunction and social life dysfunction decreased to 83.0 and 65.0–78.0 points, respectively, in individuals in their 80 s and 70–80 s, respectively; and the scores for gait disturbance decreased to 93.0 and 71.0 points for males and females in their 80 s. Overall, the median scores for pain-related and psychological disorders were 100 and 60.0–72.0 points, respectively. Conclusion: The reference values for JOABPEQ according to age and gender were established herein. Patients with low back pain should be evaluated with this new self-administered questionnaire taking these reference values into account.

Hydroxyapatite (HAp) is one of components of bone and teeth, and has an osteoconductivity. Thus, the HAp has been used as biomaterials for bone graftings. We have succeeded in development of the novel chelate-setting calcium-phosphate cement (CPC) using pure HAp particles surface-modified with inositol phosphate (IP6). While, biological apatite presented in bone and teeth of mammals contains various ions: Na+, K+, Mg2+, C1-", F" and C032-", in addition to Ca2+ and P04 ions. In this work, in order to create the chelate-setting CPC with enhanced osteoconductivity, the above-mentioned biological apatite powder (hereafter, bone HAp), instead of pure HAp, was used as a starting powder for fabrication of the chelate-setting cement. The biocompatibility of the resulting chelate-setting bone HAp cement (hereafter, IP6-bone HAp cement) was examined using a rabbit's tibia model. When the living reaction to hard tissue was histologically examined after 4 weeks implantation, we could observe that newly-formed bone directly bonded to the surface of the specimen. The newly-formed bone was also present around the cement specimen. The amounts of newly-formed bone around IP6-bone HAp cement was about 1.5 times those around IP6-pure HAp cement without bone minerals. The above findings demonstrate that the present IP6-bone HAp cements are one of the promising candidates as novel CPC with enhanced osteoconductivity.

Frozen shoulder is a relatively common disorder that leads to severe pain and stiffness in the shoulder joint. Although this disorder is self-limiting in nature, the symptoms often persist for years, resulting in severe disability. Recent studies using human specimens and animal models have shown distinct changes in the gene expression patterns in frozen shoulder tissue, indicating that novel therapeutic intervention could be achieved by controlling the genes that are potentially involved in the development of frozen shoulder. To achieve this goal, it is imperative to develop a reliable animal joint contracture model in which gene expression can be manipulated by gene targeting and transgenic technologies. Here, we describe a novel shoulder contracture mouse model. We found that this model mimics the clinical presentation of human frozen shoulder and recapitulates the changes in the gene expression pattern and the histology of frozen shoulder and joint contracture in humans and other larger animal models. The model is highly reproducible, without any major complications. Therefore, the present model may serve as a useful tool for investigating frozen shoulder etiology and for identifying its potential target genes.

Purpose. Minimally invasive spine stabilization (MISt) procedures, including MIS-transforaminal lumbar interbody fusion (MIS-TLIF), rely on precise placement of percutaneous pedicle screws (PPS). Serious intraoperative complications associated with PPS placement include great vessel and bowel injuries due to the guide-wire's anterior migration and penetration through the anterior aspect of the vertebral body. To address this issue, we developed a novel percutaneous guide wire (S-wire) and compared the biomechanical characteristics of S-wire and conventional wire in cadaveric spines, and to evaluate the S-wire's efficacy and safety in a clinical trial. Methods. The S-wire is hollow, with braided wires extending at one tip. We compared the push-out and penetration forces of the S-wire and conventional wire in fresh cadaveric lumbar spines, from L1 to L5. Results. Push-out forces caused the braided tip of the S-wire to bend or spread, and thus to resist anterior migration. The mean push-out forces for the S-wire and conventional wire were 15.5 ± 1.9 and 5.7 ± 0.8 N, respectively (P <.0001); the mean penetration forces were 69.1 ± 4.2 and 37.1± 4.8 N, respectively (P <.0005). There was no wire breakage or anterior-wall penetration in a clinical trial of 922 S-wires; interestingly, the pull-out force increased in 780 (84.6%) S-wires after placement. Conclusions. The mean push-out and penetration forces for the S-wire were approximately 3 and 2 times greater than those of conventional wire, respectively. The S-wire effectively prevented guide-wire anterior migration and penetration of the anterior vertebral-body wall. The S-wire device should effectively improve the safety of MISt procedures, including MIS-TLIF and percutaneous kyphoplasty in selected patient with osteoporosis.

Purpose: Bone tunnel creation techniques influence the 3-dimensional (3D) position of bone tunnels and graft-bending angle in anterior cruciate ligament (ACL) reconstruction. This study assessed graft-bending angle and 3D characteristics of femoral bone tunnels and compared them between outside-in (OI) and transportal (TP) techniques. Methods: Participants comprised 64 patients who underwent anatomic double-bundle ACL reconstruction, allocated to OI and TP groups (n = 32 each). The graft orientation plane exhibiting the largest graft-bending angle at the femoral tunnel aperture with the knee in extension was reconstructed from CT data using 3D imaging software. In this plane, graft-bending angle was compared between the OI and TP techniques. Results: Although positionings of the intra-articular apertures of the femoral and tibial bone tunnels were similar, several spatial parameters of bone tunnels differed between techniques. Graft-bending angles of both anteromedial and posterolateral bundles were significantly more acute with the OI technique than with the TP technique. On coronal-plane CT, angle of the bone tunnel axis relative to the distal condylar axis correlated negatively with graft-bending angle, while in the axial plane, angle of the bone tunnel axis relative to the posterior condylar axis correlated positively with graft-bending angle. Lysholm score, pivot shift test, and anteroposterior laxity at >2.5-year follow-up demonstrated no significant differences between techniques. Discussion: Different bone tunnel directions in OI and TP techniques substantially affected graft-bending angle, despite similar positionings of the intra-articular apertures. Graft-bending angle with the OI technique was acute, but risk of posterior blowout of the lateral femoral condyle was decreased. Surgeons should create the femoral tunnel while considering an obtuse graft-bending angle without increasing the risk of posterior blowout. Level of evidence: III.

Objective. This retrospective study was designed to evaluate the outcomes of four different surgical reconstructions for extensor tendon ruptures in ulnar three fingers in 48 patients with rheumatoid arthritis. Methods. The following four techniques were performed; palmaris longus tendon grafting (PL group; n = 9), extensor indicis proprius (EIP) tendon transfers (EIP group; n = 8), end-to-side transfers with tension-reduced early mobilization (End-to-side group; n = 16), and a combination of end-to-side and EIP transfers (Combination group; n = 15). Loss of extension was evaluated to determine the mean postoperative range of motion of the metacarpophalangeal (MP) joint and clinical outcomes were categorized using modified Geldmacher criteria. Results. Combination group demonstrated the best mean MP joint extension (− 3°), followed by End-to-side group (− 12°), EIP group (− 16°), and PL group (− 21°). Combination group yielded the best clinical outcomes with all cases showing good results. Conclusions. The combination of end-to-side and EIP transfer was an effective surgical reconstruction procedure for triple fingers extension loss.

The unfolded protein response (UPR) is a cellular adaptive mechanism that is activated in response to the accumulation of unfolded proteins in the endoplasmic reticulum. The inositol-requiring protein-1α/X-box-binding protein-mediated (IRE1α/ XBP1-mediated) branch of the UPR is highly conserved and has also been shown to regulate various cell-fate decisions. Herein, we have demonstrated a crucial role for the IREα/XBP1-mediated arm of the UPR in osteoclast differentiation. Using murine models, we found that the conditional abrogation of IRE1α in bone marrow cells increases bone mass as the result of defective osteoclastic bone resorption. In osteoclast precursors, IRE1α was transiently activated during osteoclastogenesis, and suppression of the IRE1α/XBP1 pathway in these cells substantially inhibited the formation of multinucleated osteoclasts in vitro. We determined that XBP1 directly binds the promoter and induces transcription of the gene encoding the master regulator of osteoclastogenesis nuclear factor of activated T cells cytoplasmic 1 (NFATc1). Moreover, activation of IRE1α was partially dependent on Ca2+ oscillation mediated by inositol 1,4,5-trisphosphate receptors 2 and 3 (ITPR2 and ITPR3) in the endoplasmic reticulum, as pharmacological inhibition or deletion of these receptors markedly decreased Xbp1 mRNA processing. The present study thus reveals an intracellular pathway that integrates the UPR and osteoclast differentiation through activation of the IRE1α/XBP1 pathway.

The increasing number of osteoporosis patients is a pressing issue worldwide. Osteoporosis frequently causes fragility fractures, limiting activities of daily life and increasing mortality. Many osteoporosis patients take numerous medicines due to other health issues; thus, it would be preferable if a single medicine could ameliorate osteoporosis and other conditions. Here, we screened 96 randomly selected drugs targeting various diseases for their ability to inhibit differentiation of osteoclasts, which play a pivotal role in development of osteoporosis, and identified methotrexate (MTX), as a potential inhibitor. MTX is currently used to treat sarcomas or leukemic malignancies or auto-inflammatory diseases such as rheumatoid arthritis (RA) through its anti-proliferative and immunosuppressive activities; however, a direct effect on osteoclast differentiation has not been shown. Here, we report that osteoclast formation and expression of osteoclastic genes such as NFATc1 and DC-STAMP, which are induced by the cytokine RANKL, are significantly inhibited by MTX. We found that RANKL-dependent calcium (Ca) influx into osteoclast progenitors was significantly inhibited by MTX. RA patients often develop osteoporosis, and osteoclasts are reportedly required for joint destruction; thus, MTX treatment could have a beneficial effect on RA patients exhibiting high osteoclast activity by preventing both osteoporosis and joint destruction.

Diabetes mellitus (DM) is frequently accompanied by complications, such as peripheral nerve neuropathy. Schwann cells play a pivotal role in regulating peripheral nerve function and conduction velocity; however, changes in Schwann cell differentiation status in DM are not fully understood. Here, we report that Schwann cells de-differentiate into immature cells under hyperglycemic conditions as a result of sorbitol accumulation and decreased Igf1 expression in those cells. We found that dedifferentiated Schwann cells could be re-differentiated in vitro into mature cells by treatment with an aldose reductase inhibitor, to reduce sorbitol levels, or with vitaminD3, to elevate Igf1 expression. In vivo DM models exhibited significantly reduced nerve function and conduction, Schwann cell de-differentiation, peripheral nerve de-myelination,andall conditionsweresignificantly rescued by aldose reductase inhibitor or vitamin D3 administration. These findings reveal mechanisms underlying pathological changes in Schwann cells seen in DM and suggest ways to treat neurological conditions associated with this condition.

Osteosarcoma (OS) is the most frequent primary solid malignant tumor of bone. Its prognosis remains poor in the substantial proportion of patients who do not respond to chemotherapy and novel therapeutic options are therefore needed. We previously established a mouse model that mimics the aggressive behavior of human OS. Enzyme-linked immunosorbent assay-based screening of such mouse tumor lysates identified platelet-derived growth factor-BB (PDGF-BB) as an abundant soluble factor, the gene for which was expressed dominantly in surrounding non-malignant cells of the tumor, whereas that for the cognate receptor (PDGF receptor β) was highly expressed in OS cells. Platelet-derived growth factor-BB induced activation of both MEK-ERK and phosphatidylinositol 3-kinase-protein kinase B signaling pathways and promoted survival in OS cells deprived of serum, and these effects were blocked by the PDGF receptor inhibitor imatinib. However, these actions of PDGF-BB and imatinib were mostly masked in the presence of serum. Whereas imatinib alone did not manifest an antitumor effect in mice harboring OS tumors, combined treatment with imatinib and adriamycin exerted a synergistic antiproliferative effect on OS cells in vivo. These results suggest that treatment of OS with imatinib is effective only when cell survival is dependent on PDGF signaling or when imatinib is combined with another therapeutic intervention that renders the tumor cells susceptible to imatinib action, such as by inducing cellular stress.

Context: Systemic metastasis to a primary tumor of the central nervous system is uncommon. Breast carcinomas metastasizing to a possibly preexisting meningioma in the spine are reported very rarely. Study design: Case report. Findings: A 69-year-old female was referred to us with progressive gait disturbance. She had undergone a total mastectomy for carcinoma of the right breast 11 years previously. A magnetic resonance imaging of the thoracic spine showed an intra- and extradural spinal cord tumor. The patient underwent resection of the tumor via laminectomy from T2 to T4. After the operation, the patient's neurological status improved significantly, and she was able to walk without assistance. Histological examination showed the tumor to be a fibrous-type meningioma within a metastatic breast cancer tumor. The patient underwent 40 Gy radiation treatment for local control of the tumor. However, the tumor recurred locally 7 months after the surgery. The patient died of carcinomatous pleurisy 13 months after the surgery. Conclusion: This case illustrates that a primary meningioma in the thoracic spine can be a recipient of breast cancer metastasis, which may alter the treatment strategy.

Bone mass is tightly controlled by a balance between osteoclast and osteoblast activities. Although these cell types mature via different pathways, some factors reportedly regulate differentiation of both. Here, in a search for factors governing osteoblastogenesis but also expressed in osteoclasts to control both cell types by one molecule, we identified B cell lymphoma 6 (Bcl6) as one of those factors and show that it promotes osteoblast differentiation. Bcl6 was previously shown to negatively regulate osteoclastogenesis. We report that lack of Bcl6 results in significant inhibition of osteoblastogensis in vivo and in vitro and in defects in secondary ossification center formation in vivo. Signal transducer and activator of transcription 1 (Stat1) reportedly attenuates osteoblast differentiation by inhibiting nuclear translocation of runt-related transcription factor 2 (Runx2), which is essential for osteoblast differentiation. We found that lack of Bcl6 resulted in signifi cant elevation of Stat1 mRNA and protein expression in osteoblasts and showed that Stat1 is a direct target of Bcl6 using a chromatin immune-precipitation assay. Mice lacking both Bcl6 and Stat1 (DKO) exhibited significant rescue of bone mass and osteoblastic parameters as well as partial rescue of secondary ossification center formation compared with Bcl6-de ficient mice in vivo. Altered osteoblastogenesis in Bcl6-defi cient cells was also restored in DKO in vitro. Thus, Bcl6 plays crucial roles in regulating both osteoblast activation and osteoclast inhibition.

Interleukin (IL)-1 is one of the most evolutionarily conserved cytokines and plays an essential role in the regulation of innate immunity. IL-1 binds to two different receptors, IL-1R1 and IL-1R2, which share approximately 28% amino acid homology. IL-1R1 contains a cytoplasmic domain and is capable of transducing cellular signals; by contrast, IL-1R2 lacks a functional cytoplasmic domain and serves as a decoy receptor for IL-1. Interestingly, IL-1R2 is proteolytically cleaved and also functions as a soluble receptor that blocks IL-1 activity. In the present study, we examined the shedding properties of IL-1R2 and demonstrate that ADAM17 is de facto the major sheddase for IL-1R2 and that introducing a mutation into the juxta-membrane domain of IL-1R2 significantly desensitizes IL-1R2 to proteolytic cleavage. IL-1R1 was almost insensitive to ADAM17-dependent cleavage; however, the replacement of the juxta-membrane domain of IL-R1 with that of IL-1R2 significantly increased the sensitivity of IL-1R1 to shedding. Furthermore, we demonstrate that ADAM17 indirectly enhances IL-1 signaling in a cell-autonomous manner by selectively cleaving IL-1R2. Taken together, the data collected in the present study indicate that ADAM17 affects sensitivity to IL-1 by changing the balance between IL-1R1 and the decoy receptor IL-1R2.