OA10 is a novel p38alpha mitogen-activated protein kinase inhibitor that suppresses osteoclast differentiation and bone resorption.

In search of anti-bone resorbing agents for the potential treatment of osteoporosis, we synthesized a novel compound Tert-butyl 4-(3-[1H-indole-2-carboxamido]benzoyl)piperazine-1-carboxylate (OA10) and found that OA10 is capable of inhibiting RANKL-mediated osteoclast formation and osteoclastic bone resorption in a dose-dependent manner. This biological effect is further supported by the fact that OA10 suppressed osteoclastic-specific gene expression, including tartrate-resistant acid phosphatase, cathepsin K receptor, and calcitonin receptor. Further molecular mechanism investigation revealed OA10 inhibited p38 phosphorylation, suppressed c-fos and NFATc1 expression without affecting NF-κB or JNK signaling pathways. Taken together, this study suggested that OA10 can inhibit osteoclastogenesis by suppressing p38-c-Fos-NFATc1 cascade. OA10 may be developed as a therapeutic drug for osteoclast-related osteolytic diseases.

The arch structure of trabeculae in normal femoral head and its biomechanical significance.

The microstructure of the normal human femoral head was observed under light and electron microscope. Most of the trabeculae were seen in the form of arch structure, and the collagen fibers and mineral columns among the trabeculae were arranged in different directions. These findings provide a new explanation of the mechanism by which the femoral head can bear high stress without collapse.

Effect of internal fixation plates on microcirculation in under-plate cortical bones. Microangiography and scanning electronmicroscopy.

To elucidate the effect of the internal fixation plates on the local bone blood supply, we used microangiography and scanning electron microscopy to observe the morphological changes of microcirculation in the cortical bones obtained from intact rabbit tibiae on which plates of two different stiffness had been fixed for comparison. The results indicated that both rigid stainless steel plate and less rigid methyl methacrylate plate could induce the bone microcirculation under the plate to undergo a process from early depression to late reactive recruitment. The features of the microcirculation recruitment such as vascular number, arrangement and dilatation varied with plates of different stiffness and were more obvious in the cortex fixed by rigid stainless steel plate.

Repair of regional osteoporosis after removal of rigid fixing plate. An experimental investigation.

Twenty-four New Zealand white rabbits were plated on their intact left tibiae with stainless steel plates and 4 animals served as controls. The plates were removed 2 months after implantation in 20 plated animals. Of them, 4 were sacrificed immediately after plate removal and the other 16 were killed in successive groups with 4 in each group 1,2,3 and 4 months after plate removal respectively. The remaining 4 plated animals were killed at 6 months after implantation. Bone samples under the plates were harvested and prepared for polarized light microscopy to investigate the repair of the regional osteoporosis induced by rigid implant. The results indicated that the regional osteoporosis could recover gradually after plate removal. The repair process manifested itself mainly as the repair of resorption cavities and the remodeling of collagen fibers. The orientation of the collagen fibers remained disorganized when the resorption cavities had been repaired. It is suggested that delayed restoration of bone structure might be one of the potential causes of refracture after removal of the rigid implant.

Bone remodelling after internal fixation with different stiffness plates: ultrastructural investigation.

Forty adult New Zealand rabbits were used in this experiment. Four rabbits served as control and the rest 36 being divided into 3 groups, each of which was fixed respectively with methylmethacrylate, titanium alloy and stainless steel plate on the left intact tibiae. The cortical bone beneath the plate was harvested at 2, 4, 8 and 12 weeks after operation and observed by means of using transmission electron microscope. The major ultrastructural changes after internal fixation with different stiffness plates were alteration of osteocyte life cycle, perilacunar matrix and disorder of osteoblast and osteoblast coupling. The greater the stiffness of the plate, the greater the ultrastructural change.

Application of a NiTi staple in the metatarsal osteotomy.

Thirty-six metatarsal osteotomies using internal fixation of a shape memory metal compression staple for hallux valgus were performed in 21 women with a mean age of 42.3 years (30-66 years). The time for return to light work averaged 19.0 days, and to full work and normal walk 41.2 days after the operation. Twenty patients (35 feet) had complete relief from pain. Only in one foot, the pain was transferred under the second metatarsal head. The appearance of the feet was apparently improved and the width of the forefeet was decreased by a mean of 0.90 cm after the operation. Radiographic analysis of feet showed that all osteotomies united, and the average angle of hallux valgus was improved from 31.2 degrees to 16.3 degrees and the mean intermetatarsal angle from 12.0 degrees to 6.4 degrees. No external fixation of plaster splintage was needed and the distal fragment during healing of the osteotomy was stable. The time of bone healing was shortened and patients were allowed to bear weight at an early time.

The use of nickel-titanium alloy in orthopedic surgery in China.

A new biomaterial made of nickel and titanium with its shape-memory characteristics has been manufactured, investigated, and used in Shanghai, China. Since 1981, this biomaterial has been used in 265 cases clinically, among which 71 involved orthopedic surgery. Results are satisfactory without failure in our short-term follow up. This preliminary report of the use of this new biomaterial with the unique characteristic of being able to recover to its original shape with particular transformation temperatures indicates its potential for opening a new field for investigation in surgery. Research to discover appropriate ratios of nickel and titanium for specific usage is underway. The interest and cooperation between the medical and engineering professions may eventually solve the problems through mutual efforts and result in improved shape-memory biomaterials.

[An experimental study of the process of bony ingrowth into inorganic bone-particle impregnated bone cement].

A composite of inorganic bone particles formed with bone cement in certain proportion was implanted in the proximal femora of 15 New Zealand rabbits. The animals were sacrificed in batches at different intervals after implantation and specimens were sectioned for scanning electron microscopic (SEM) observation and push-out test. SEM showed that the bone particles in the composite were in contact with each other and forming bony pathways. The gaps between inorganic bone particle bone cement and cortical bone were filled at first with collagen fibrils which were interwoven to form collagen fiber bundles and then mineralized to assume woven bone. The bone particles became smaller in size and were enveloped, absorbed and replaced by new bone structure gradually reaching the depth of bone cement along the pathways formed by bone particles. The shear strength of the cement-bone interface was increased subsequently.

[Thoracoplasty in scoliosis].

Since 1978, 108 cases of scoliosis with severe thoracic deformity have received thoracoplasty. Most of them were operated at the same time for correction of scoliosis. The resected ribs were served as bone graft for posterial spinal fusion. The rib prominence was reduced 2.5-6.9 cm after operation, and the costectomy also found to be beneficial to the correction of lateral curvature and axial rotation of the spine. The thoracoplasty showed no affect upon the pulmonary function. In this paper, three kinds of thoracoplasty and their indications are discussed and compared.

[An in vivo study of inorganic bone particle-impregnated bone cement].

According to definite proportion by weight, inorganic bone particles were impregnated into bone cement and then used for the fixation of implanted artificial femoral head in a series of canines. Upon successive observations, new bone was seen to have already been growing into the bone cement one month post operatively, and active growth going on with bone tissue passing through the whole layer of cement three months after operation. In the fifth month's specimens, most of the inorganic bone particles were replaced by new bone tissue while slices of one year post operation showed that the bone tissue was mature and the activity of bone formation ceased. The biological fixation effect produced by bone ingrowth was found to have increased the shearing strength of cement-bone interface to 1.4-3.6 times of the control side and the stability of prosthesis was improved obviously. The bone-particle-impregnated bone cement has already been using in our clinical practice since 1987.

[Comparative study of three different hip function evaluation systems].

Harris's, Charnley's and Beijing's numerical rating systems were used to evaluate the functional results of 42 cases of bipolar type artificial femoral head replacement. The results of assessment of the three methods were compared statistically and proved that the results are comparable. Before the overall evaluation, the patients should be divided into three groups (according to Charnley's method) on the basis of their original capacity of locomotion. The score results of the three groups should not be mixed up. The calculation method of total score of Beijing system may need certain modification. The advantages and disadvantages of the three systems, the significance of capacity assessment of daily activity and radiological evaluation are discussed on the basis of the results of analysis.

[An experimental study and preliminary clinical report of shape-memory sawtooth-arm embracing internal fixator].

The sawtooth-arm internal embracing fixator is made of Nickel-Titanium shape memory alloy and consists of 3 components: body, arms and sawteeth. In cross section a 2/3 circumference is constructed by body and arms of the fixator. The free ends of the arms which exceed the semi-circle are bent more medially so that it can match the requirement of fixation of long tubular bone whose cross section is not a regular circle. The embracing fixator has two types: the cylinder type is for use in the middle part and the cone type is either for the proximal or distal 1/3 of the shaft of long tubular bone. The animal experimental studies and in vitro mechanical tests demonstrated that the embracing fixator possesses good anti-bending and anti-torsion effects, and its resisting compression effect was much lower than that of bone plate. These characteristics are beneficial for enhancing fracture healing, reducing post fixation osteoporosis and providing a new, simple and effective method for the treatment of long tubular bone fracture. The fixator has already been used in the treatment of fractures of femur, humerus, radius and ulna with good results.

[Clinical analysis of femoral neck fracture in 188 adult cases].

There were 188 cases of femoral neck fracture of adult below the age of fifty-five years old admitted to our hospital from 1974 to 1989, including 152 cases of fresh fracture, 36 old fracture. The rate of femoral head necrosis after fracture was 11.8 percent in the group of patients under fifty years of age, and 9.8 percent in patients between fifty-one and fifty five years old. The operation adopted in our series was mainly the percutaneous screw-thread pinning for internal fixation. Bone graft transplantation with the pedicle of quadratus femoris muscle was simultaneously performed in some cases, 26.7 percent in patients between the age of fifteen and twenty, along with the increase of age the patient number for transplantation decreased, only 7.8 percent in patients between the age of fifty-one and fifty-five. The author suggests that in treatment of femoral neck fracture of adult generally should not consider the use of artificial prosthesis replacement. We should decide according to the patients general and local status as the basis for the choice of a reasonable internal fixation, and consider whether an operation should be performed to further improve blood circulation of the femoral head.

OA-4 inhibits osteoclast formation and bone resorption via suppressing RANKL induced P38 signaling pathway.

Osteoclasts are one of the key therapeutic targets for a variety of orthopedic diseases such as osteoporosis and osteoarthritis. In this study, we synthesized a novel compound N-(3-(cyclohexylcarbamoyl) phenyl)-1H-indole-2- carboxamide (termed as OA-4) and investigated the effects of OA-4 on the differentiation and function of osteoclasts. OA-4 markedly diminished osteoclast differentiation and osteoclast specific gene expression in a dose-dependent manner. In addition, OA-4 dose-dependently suppressed osteoclastic bone resorption. Furthermore, we found OA-4 attenuated RANKL-induced p38 phosphorylation without affecting JNK or NF-κB signaling pathways. Collectively, we synthesized a novel compound OA-4 which can inhibit osteoclast formation and functions via the suppression of p38 signaling pathway.

Andrographolide suppresses RANKL-induced osteoclastogenesis in vitro and prevents inflammatory bone loss in vivo.

BACKGROUND AND PURPOSE: Osteoclasts play a pivotal role in diseases such as osteoporosis, rheumatoid arthritis and tumour bone metastasis. Thus, searching for natural compounds that may suppress osteoclast formation and/or function is promising for the treatment of osteoclast-related diseases. Here, we examined changes in osteoclastogenesis and LPS-induced osteolysis in response to andrographolide (AP), a diterpenoid lactone isolated from the traditional Chinese and Indian medicinal plant Andrographis paniculata. EXPERIMENTAL APPROACH: Effects of AP on osteoclast differentiation and bone resorption were measured in vitro. Western blots and RT-PCR techniques were used to examine the underlying molecular mechanisms. The bone protective activity of AP in vivo was assessed in a mouse model of osteolysis. KEY RESULTS: AP concentration-dependently suppressed RANKL-mediated osteoclast differentiation and bone resorption in vitro and reduced the expression of osteoclast-specific markers, including tartrate-resistant acid phosphatase, calcitonin receptors and cathepsin K. Further molecular analysis revealed that AP impaired RANKL-induced NF-κB signalling by inhibiting the phosphorylation of TGF-ß-activated kinase 1, suppressing the phosphorylation and degradation of IκBα, and subsequently preventing the nuclear translocation of the NF-κB p65 subunit. AP also inhibited the ERK/MAPK signalling pathway without affecting p38 or JNK signalling. CONCLUSIONS AND IMPLICATIONS: AP suppressed RANKL-induced osteoclastogenesis through attenuating NF-κB and ERK/MAPK signalling pathways in vitro, thus preventing bone loss in vivo. These data indicated that AP is a promising natural compound for the treatment of osteoclast-related bone diseases.

V-ATPases in osteoclasts: structure, function and potential inhibitors of bone resorption.

The vacuolar-type H(+)-ATPase (V-ATPase) proton pump is a macromolecular complex composed of at least 14 subunits organized into two functional domains, V(1) and V(0). The complex is located on the ruffled border plasma membrane of bone-resorbing osteoclasts, mediating extracellular acidification for bone demineralization during bone resorption. Genetic studies from mice to man implicate a critical role for V-ATPase subunits in osteoclast-related diseases including osteopetrosis and osteoporosis. Thus, the V-ATPase complex is a potential molecular target for the development of novel anti-resorptive agents useful for the treatment of osteolytic diseases. Here, we review the current structure and function of V-ATPase subunits, emphasizing their exquisite roles in osteoclastic function. In addition, we compare several distinct classes of V-ATPase inhibitors with specific inhibitory effects on osteoclasts. Understanding the structure-function relationship of the osteoclast V-ATPase may lead to the development of osteoclast-specific V-ATPase inhibitors that may serve as alternative therapies for the treatment of osteolytic diseases.