Kousuke Iba

Mice with a Targeted Deletion of the Tetranectin Gene Exhibit a Spinal Deformity

ABSTRACT Tetranectin is a plasminogen-binding, homotrimeric protein belonging to the C-type lectin family of proteins. Tetranectin has been suggested to play a role in tissue remodeling, due to its ability to stimulate plasminogen activation and its expression in developing tissues such as developing bone and muscle. To test the functional role of tetranectin directly, we have generated mice with a targeted disruption of the gene. We report that the tetranectin-deficient mice exhibit kyphosis, a type of spinal deformity characterized by an increased curvature of the thoracic spine. The kyphotic angles were measured on radiographs. In 6-month-old normal mice (n= 27), the thoracic angle was 73° ± 2°, while in tetranectin-deficient 6-month-old mice (n = 35), it was 93° ± 2° (P < 0.0001). In approximately one-third of the mutant mice, X-ray analysis revealed structural changes in the morphology of the vertebrae. Histological analysis of the spines of these mice revealed an apparently asymmetric development of the growth plate and of the intervertebral disks of the vertebrae. In the most advanced cases, the growth plates appeared disorganized and irregular, with the disk material protruding through the growth plate. Tetranectin-null mice had a normal peak bone mass density and were not more susceptible to ovariectomy-induced osteoporosis than were their littermates as determined by dual-emission X-ray absorptiometry scanning. These results demonstrate that tetranectin plays a role in tissue growth and remodeling. The tetranectin-deficient mouse is the first mouse model that resembles common human kyphotic disorders, which affect up to 8% of the population.

The serum level of bone-specific alkaline phosphatase activity is associated with aortic calcification in osteoporosis patients.

It has been suggested that there are several possible linkages between vascular calcification and osteoporosis. In addition, the processes of vascular calcification may have a common etiology with bone formation. Thus, we hypothesized that the serum levels of bone metabolic markers would be different between osteoporosis patients with and without vascular calcification. In this study, we showed that the serum level of bone-specific alkaline phosphatase activity in osteoporosis patients with abdominal aortic calcification had a higher value than in those without the calcification. On the other hand, there were no significant differences in the urine levels of type I collagen cross-linked N-telopeptides (a bone resorption marker), or in the serum levels of intact osteocalcin, Ca, and P. Bone-specific alkaline phosphatase is the most important marker for osteoblast differentiation; furthermore, the serum level of its activity may reflect the process of calcification of the aorta in osteoporosis patients.

IGF-I regulates tight-junction protein claudin-1 during differentiation of osteoblast-like MC3T3-E1 cells via a MAP-kinase pathway.

Insulin-like growth factor I (IGF-I) is expressed in many tissues, including bone, and acts on the proliferation and differentiation of osteoblasts as an autocrine/paracrine regulator. Tight-junction proteins have been detected in osteoblasts, and direct cell-to-cell interactions may modulate osteoblast function with respect, for example, to gap junctions. In order to investigate the regulation of expression of tight-junction molecules and of function during bone differentiation, osteoblast-like MC3T3-E1 cells and osteocyte-like MLO-Y4 cells were treated with IGF-I. In both MC3T3-E1 cells and MLO-Y4 cells, the tight-junction molecules occludin, claudin-1, -2, and -6, and the gap-junction molecule connexin 43 (Cx43) were detected by reverse transcription with polymerase chain reaction. In MC3T3-E1 cells but not MLO-Y4 cells, mRNAs of claudin-1, -2, and -6, Cx43, and type I collagen, and proteins of claudin-1 and Cx43 were increased after treatment with IGF-I. Such treatment significantly decreased paracellular permeability in MC3T3-E1 cells. The expression of claudin-1 in MC3T3-E1 cells after IGF-I treatment was mainly upregulated via a mitogen-activated protein (MAP)-kinase pathway and, in part, modulated by a PI3-kinase pathway, whereas Cx43 expression and the mediated gap-junctional intercellular communication protein did not contribute to the upregulation. Furthermore, in MC3T3-E1 cells during wound healing, upregulation of claudin-1 was observed together with an increase of IGF-I and type I collagen. These findings suggest that the induction of tight-junction protein claudin-1 and paracellular permeability during the differentiation of osteoblast-like MC3T3-E1 cells after treatment with IGF-I is regulated via a MAP-kinase pathway, but not with respect to gap junctions.

Improvement of pain and regional osteoporotic changes in the foot and ankle by low-dose bisphosphonate therapy for complex regional pain syndrome type I: a case series

IntroductionComplex regional pain syndrome is characterized by pain, allodynia, hyperalgesia, edema, signs of vasomotor instability, movement disorders, joint stiffness, and regional osteopenia. It is recognized to be difficult to treat, despite various methods of treatment, including physiotherapy, calcitonin, corticosteroids, sympathetic blockade, and nonsteroidal anti-inflammatory drugs. Pathophysiologically, complex regional pain syndrome reveals enhanced regional bone resorption and high bone turnover, and so bisphosphonates, which have a potent inhibitory effect on bone resorption, were proposed for the treatment of complex regional pain syndrome.Case presentationA 48-year-old Japanese man with complex regional pain syndrome type I had severe right ankle pain with a visual analog scale score of 59 out of 100 regardless of treatment with physiotherapy and nonsteroidal anti-inflammatory drugs for five months. Radiographs showed marked regional osteoporotic changes and bone scintigraphy revealed a marked increase in radioactivity in his ankle. One month after the start of oral administration of risedronate (2.5 mg per day), his bone pain had fallen from a VAS score of 59 out of 100 to 18 out of 100. Bone scintigraphy at 12 months showed a marked reduction in radioactivity to a level comparable to that in his normal, left ankle. On the basis of these results, the treatment was discontinued at 15 months. At 32 months, our patient had almost no pain and radiographic findings revealed that the regional osteoporotic change had returned to normal.A second 48-year-old Japanese man with complex regional pain syndrome type I had severe right foot pain with a visual analog scale score of 83 out of 100 regardless of treatment with physiotherapy and nonsteroidal anti-inflammatory drugs for nine months. Radiographs showed regional osteoporotic change in his phalanges, metatarsals, and tarsals, and bone scintigraphy revealed a marked increase in radioactivity in his foot. One month after the start of oral administration of alendronate (35 mg per week), his bone pain had fallen from a visual analog scale score of 83 out of 100 to 30 out of 100 and, at nine months, was further reduced to 3 out of 100. The treatment was discontinued at 15 months because of successful pain reduction. At 30 months, our patient had no pain and the radiographic findings revealed marked improvement in regional osteoporotic changes.ConclusionsWe believe low-dose oral administration of bisphosphonate is worth considering for the treatment of idiopathic complex regional pain syndrome type I accompanied by regional osteoporotic change.

Horse-related injuries in a thoroughbred stabling area in Japan.

Abstract To investigate the demographic details and patterns of injuries related to horse handling, we reviewed 637 horse-related injuries in 581 stable- or stud-workers in a representative area of thoroughbred stabling in Japan. We found that (1) injuries occurred most frequently in a group of a relatively young workers, with a seasonal variation; (2) the principal mechanism of injury was kicks, which accounted for 39.2% of all injuries, including 11 serious and one lethal visceral injuries; (3) the upper half of the body was more frequently involved than the lower half; and (4) the peripheral bones (hand and foot) and the ribs accounted for more than half of 148 fractures. These findings are distinct from those in horse-riding injuries reported in the literature and emphasize the importance in developing preventive strategies specifically for workers in horse stables.

The relationship between the pressure adjacent to the ulnar nerve and the disease causing cubital tunnel syndrome

We investigated the relationship between cubital tunnel pressure in patients with cubital tunnel syndrome with osteoarthritis and those without osteoarthritis. We studied 31 elbows in 29 patients. We divided the patients into two groups: one associated with osteoarthritis and the other not associated with osteoarthritis. In the latter group, there was ulnar nerve subluxation in 10 elbows and cubitus valgus in 3. Cubital tunnel pressure was measured intraoperatively with a fiberoptic microtransducer. The extraneural pressure with the elbow flexed was significantly increased in patients with osteoarthritis and those without osteoarthritis. The pressure within the cubital tunnel in osteoarthritic elbows was significantly higher than that in those without osteoarthritis. Moreover, the pressure of osteoarthritic elbows significantly increased from proximally to distally within the cubital tunnel, whereas the pressure in elbows without osteoarthritis was high only proximally. Thus, cubital tunnel pressure could be a more important causative factor for cubital tunnel syndrome in the elbows with osteoarthritis than in those without osteoarthritis.

Transforming growth factor‐β 1 downregulates dexamethasone‐indunced tetranectin gene expression during the in vitro mineralization of the human osteoblastic cell line SV‐HFO

In the present study, we examined the regulation of tetranectin gene expression using a human osteoblastic cell line, SV‐HFO, that undergoes mineralization upon treatment with dexamethasone. We found that the expression of tetranectin and alkaline phosphatase mRNA was induced by dexamethasone treatment as evidenced by Northern blotting. When transforming growth factor‐β 1 (TGF‐β 1) was added together wwith dexamethasone to the SV‐HFO cell cultures, the mineralization process was markedly suppressed and the expression of tetra nectin and alkaline phosphatase was downregulated in a dosedependent manner. These results demonstrate that the expression of tetranectin in these osteoblastic cells is regulated by dexamethasone and TGF‐β 1 and that tetranectin expression is tightly linked to the process of mineralization.

Time to functional recovery after arthroscopic surgery for tennis elbow

BACKGROUND This study evaluated recovery from chronic lateral epicondylitis after arthroscopic treatment. METHODS Twenty-three consecutive patients (5 men, 18 women) with chronic lateral epicondylitis underwent arthroscopic surgery. Patients were a mean age of 49 years. Prospective outcome data were collected before the operation and at 1, 2, 3, 6, 12 and 24 months after surgery. Outcomes were assessed using a visual analog scale (VAS: 0-100), grip strength percentage (compared with the unaffected side), the Japanese Orthopaedic Association elbow score, and the Disability of the Arm, Shoulder and Hand questionnaire. RESULTS A mean VAS score at rest of 26 preoperatively improved to 8 (P = .0026), 6, and 3 at 1, 2, and 3 months after surgery, respectively. A mean VAS score during activity improved from 68 preoperatively to 35 (P < .001), 23, and 19 at 1, 2, and 3 months after surgery, respectively. Both VAS scores gradually decreased up to 24 months after surgery. The mean grip strength improved from 66.1% preoperatively to 88.7% at 2 months after surgery (P < .001). The mean Japanese Orthopaedic Association elbow score improved from 38 points preoperatively to 61 points at 1 month after surgery (P < .001). The mean Disability of the Arm, Shoulder and Hand score improved from 32 points preoperatively to 15 points at 3 months after surgery (P < .001). CONCLUSION Arthroscopic surgery for lateral epicondylitis provides significant improvement in pain and functional recovery up to 3 months after surgery. However, it takes more than 6 months for the VAS score during activity to fall below 10 points.

Inhibitory effect of bisphosphonate on osteoclast function contributes to improved skeletal pain in ovariectomized mice

The aim of this study was to evaluate skeletal pain associated with osteoporosis and to examine the inhibitory effect of bisphosphonate (BP) on pain in an ovariectomized (OVX) mouse model. We evaluated skeletal pain in OVX mice through an examination of pain-like behavior as well as immunohistochemical findings. In addition, we assessed the effects of alendronate (ALN), a potent osteoclast inhibitor, on those parameters. The OVX mice showed a decrease in the pain threshold value, and an increase in the number of c-Fos immunoreactive neurons in laminae I–II of the dorsal horn of the spinal cord. Alendronate caused an increase in the pain threshold value and inhibited c-Fos expression. The serum level of tartrate-resistant acid phosphatase 5b, a marker of osteoclast activity, was significantly negatively correlated with the pain threshold value. Furthermore, we found that an antagonist of the transient receptor potential channel vanilloid subfamily member 1, which is an acid-sensing nociceptor, improved pain-like behavior in OVX mice. These results indicated that the inhibitory effect of BP on osteoclast function might contribute to an improvement in skeletal pain in osteoporosis patients.

A significant improvement in lower limb pain after treatment with alendronate in two cases of Camurati–Engelmann disease

Camurati–Engelmann disease, also known as progressive diaphyseal dysplasia, is a rare osteosclerotic dysplasia of bone that is characterized by endosteal and periosteal thickening of the diaphysis of the long bones. The most common symptoms are severe, bilateral, and symmetrical bone pain in the limbs, waddling gait, muscle weakness, and easy fatigability [1,2]. Camurati–Engelmann disease is inherited in an autosomic dominant manner, and alterations in the sequence in the transforming growth factor-β1 (TGF-β1) gene in the chromosomal region 19q13.1 have been found to be associated with the disorder [3]. Radiographically, symmetrical osteosclerosis is observed in the diaphyses and metaphyses of the long bones [4], and bone scintigraphy reveals a marked increase in radioactivity at the affected regions [5]. These radiologic fi ndings provide a meaningful assessment of disease extent and activity. A few previous reports showed that biochemical markers of bone turnover were useful to evaluate the disease activity of Camurati–Engelmann disease [6]. Concerning the treatment of Camurati–Engelmann disease, corticosteroids have been reported to be effective in reducing the symptoms in some cases [7], whereas there were no defi nitive data on the effectiveness of corticosteroids on disease activity in a previous report [8]. Recently, several reports showed that bisphosphonates have been used in Camurati–Engelmann disease because of the experience of treatment with these drugs in Paget’s disease. However, most of the studies indicated that the administration of bisphosphonates was ineffective for treating Camurati–Engelmann disease [8–10]. In this study, treatment of two cases of Camurati–Engelmann disease was attempted with alendronate. The drug markedly improved bone pain, and a correlative decrease in cross-linked Ntelopeptides of type I collagen (NTX), a bone resorption marker, was noted.