Mechanobiology of bone tissue

In order to obtain bones that combine a proper resistance against mechanical failure with a minimum use of material, bone mass and its architecture are continuously being adapted to the prevailing mechanical loads. It is currently believed that mechanical adaptation is governed by the osteocytes, which respond to a loading-induced flow of interstitial fluid through the lacuno-canalicular network by producing signaling molecules. An optimal bone architecture and density may thus not only be determined by the intensity and spatial distribution of mechanical stimuli, but also by the mechanoresponsiveness of osteocytes. Bone cells are highly responsive to mechanical stimuli, but the critical components in the load profile are still unclear. Whether different components such as fluid shear, tension or compression may affect cells differently is also not known. Although both tissue strain and fluid shear stress cause cell deformation, these stimuli might excite different signaling pathways related to bone growth and remodeling. In order to define new approaches for bone tissue engineering in which bioartificial organs capable of functional load bearing are created, it is important to use cells responding to the local forces within the tissue, whereby biophysical stimuli need to be optimized to ensure rapid tissue regeneration and strong tissue repair.     

Low-intensity ultrasound stimulates endochondral ossification in vitro.

Animal and clinical studies have shown an acceleration of bone healing by the application of low-intensity ultrasound. The objective of this study was to examine in vitro the influence of low-intensity ultrasound on endochondral ossification of 17-day-old fetal mouse metatarsal rudiments. Forty-six triplets of paired metatarsal rudiments were resected 'en block' and cultured for 7 days with and without low-intensity ultrasound stimulation (30 mw/cm2). At days 1, 3, 5, and 7, the total length of the metatarsal rudiments, as well as the length of the calcified diaphysis were measured. Histology of the tissue was performed to examine its vitality. The increase in length of the calcified diaphysis during 7 days of culture was significantly higher in the ultrasound-treated rudiments compared to the untreated controls (P = 0.006). The growth of the control diaphysis was 180 +/- 30 microm (mean +/- SEM), while the growth of the ultrasound-treated diaphysis was 530 +/- 120 microm. The total length of the metatarsal rudiments was not affected by ultrasound treatment. Histology revealed a healthy condition of both ultrasound-treated and control rudiments. In conclusion, low-intensity ultrasound treatment stimulated endochondral ossification of fetal mouse metatarsal rudiments. This might be due to stimulation of activity and/or differentiation of osteoblasts and hypertrophic chondrocytes. Our results support the hypothesis that low-intensity ultrasound activates ossification via a direct effect on osteoblasts and ossifying cartilage.     

Associations between perception of wellness and health‐related quality of life,comorbidities, modifiable lifestyle factors and demographics in older Australians

Aim: The associations between perceived wellness and health‐related quality of life, comorbidities and modifiable lifestyle factors in older adults were explored. Methods: Self‐administered questionnaires including the Perceived Wellness Survey and the 36‐Item Short Form of the Medical Outcomes Study version two were distributed to 328 community‐living adults aged 65 years and over. Results: Results showed positive associations between perception of wellness and health‐related quality of life. General health (r(249) = 0.66, P < 0.01), vitality (r(249) = 0.59, P < 0.01) and mental health (r(249) = 0.52, P < 0.01) had the strongest association with perceived wellness; and social functioning (r(249) = 0.3, P < 0.01) and pain (r(249) = 0.36, P < 0.01) the lowest. Perceived wellness was influenced by hearing, mobility, memory, chronic disease, exercise, gambling and single status. Conclusion: The study identified that perceived wellness in older adults is a multidimensional construct.     

Reaming debris as a novel source of autologous bone to enhance healing of bone defects

Reaming debris is formed when bone defects are stabilized with an intramedullary nail, and contains viable osteoblast-like cells and growth factors, and might thus act as a natural osteoinductive scaffold. The advantage of using reaming debris over stem cells or autologous bone for healing bone defects is that no extra surgery is needed to obtain the material. To assess the clinical feasibility of using reaming debris to enhance bone healing, we investigated whether reaming debris enhances the healing rate of a bone defect in sheep tibia, compared to an empty gap. As golden standard the defect was filled with iliac crest bone. Bones treated with iliac crest bone and reaming debris showed larger callus volume, increased bone volume, and decreased cartilage volume in the fracture gap, and increased torsional toughness compared to the empty gap group at 3 weeks postoperative. In addition, bones treated with reaming debris showed increased torsional stiffness at 6 weeks postoperatively compared to the empty defect group, while bending stiffness was marginally increased. These results indicate that reaming debris could serve as an excellent alternative to iliac crest bone for speeding up the healing process in bone defects that are treated with an intramedullary nail.     

Mechanical Loading Stimulates BMP7, But Not BMP2, Production by Osteocytes

Bone mechanical adaptation is a cellular process that allows bones to adapt their mass and structure to mechanical loading. This process is governed by the osteocytes, which in response to mechanical loading produce signaling molecules that affect osteoblasts and osteoclasts. Bone morphogenic proteins (BMPs) are excellent candidates as signaling molecules, but it is unknown whether mechanically stimulated osteocytes affect bone adaptation through BMP production. Therefore, the aim of this study was to assess whether osteocytes produce BMPs in response to mechanical loading. In addition, since BMP7 has a vitamin D receptor (VDR) response element in the promoter region, we also investigated whether VDR is involved in the BMP7 response to mechanical loading. Human or VDR^−/− mouse primary bone cells were submitted in vitro to 1 h pulsating fluid flow (PFF) and postincubated without PFF (PI) for 1–24 h, and gene and protein expression of BMP2 and BMP7 were quantified. In human bone cells, PFF did not change BMP2 gene expression, but it upregulated BMP7 gene expression by 4.4- to 5.6-fold at 1–3 h PI and stimulated BMP7 protein expression by 2.4-fold at 6 h PI. PFF did not stimulate BMP7 gene expression in VDR^−/− mouse bone cells. These results show for the first time that mechanical loading upregulates BMP7, likely via the VDR, but not BMP2, gene and protein expression in osteocytes in vitro. Since BMP7 plays a major role in bone development and remodeling, these data might contribute to a better understanding of the mechanism leading to the mechanical adaptation of bone.     

Fourteen new cases contribute to the characterization of the 7q11.23 microduplication syndrome

Interstitial deletions of 7q11.23 cause Williams–Beuren syndrome, one of the best characterized microdeletion syndromes. The clinical phenotype associated with the reciprocal duplication however is not well defined, though speech delay is often mentioned. We present 14 new 7q11.23 patients with the reciprocal duplication of the Williams–Beuren syndrome critical region, nine familial and five de novo. These were identified by either array-based MLPA or by array-CGH/oligonucleotide analysis in a series of patients with idiopathic mental retardation with an estimated population frequency of 1:13,000–1:20,000. Variable speech delay is a constant finding in our patient group, confirming previous reports. Cognitive abilities range from normal to moderate mental retardation. The association with autism is present in five patients and in one father who also carries the duplication. There is an increased incidence of hypotonia and congenital anomalies: heart defects (PDA), diaphragmatic hernia, cryptorchidism and non-specific brain abnormalities on MRI.Specific dysmorphic features were noted in our patients, including a short philtrum, thin lips and straight eyebrows. Our patient collection demonstrates that the 7q11.23 microduplication not only causes language delay, but is also associated with congenital anomalies and a recognizable face.     

Effects of two inhibitors of anion transport on bone resorption in organ culture

The present investigation was undertaken to examine the effects of 4-acetamido-4'-isothiocyanostilbene-2,2-disulfonic acid (SITS) and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), known amino-reactive and selective inhibitors of anion exchange across the plasma membrane, on bone resorption in organ cultures of fetal rat long bones. Cultures were treated with SITS and DIDS under control unstimulated conditions or with PTH. Both SITS and DIDS were found to be potent inhibitors of 45Ca release from previously labeled fetal rat long bones. Both control resorption and the response to PTH were inhibited in a dose-related fashion. SITS and DIDS also inhibited the incorporation of [3H]thymidine in bone. The effects on resorption and [3H]thymidine incorporation were reversible when the drugs were withdrawn. These findings indicate that SITS and DIDS are potent inhibitors of bone resorption which may act by blocking the anion exchange, Cl-/HCO3-.