Subchondral osteopenia and accelerated bone remodelling post-ovariectomy - a possible mechanism for subchondral microfractures in the aetiology of spontaneous osteonecrosis of the knee?

Osteopenia and subchondral microfractures are implicated in the aetiology of spontaneous osteonecrosis of the knee. The ovine tibia shows significant alterations of the trabecular architecture within the subchondral bone of the medial tibial plateau post-ovariectomy, including reduced trabecular bone volume fraction. We hypothesise that accelerated subchondral bone resorption may also play a role in increasing microfracture risk at this site. 23 sheep were examined in this study; 10 of the sheep underwent ovariectomy (OVX), while the remainder (n=13) were kept as controls (CON). Five fluorochrome dyes were administered intravenously at 12 week intervals via the jugular vein to both groups, to label sites of bone turnover. These animals were then sacrificed at 12 months post-operatively. Bone turnover was significantly increased in the OVX group in both trabecular bone (2.024 vs. 1.047, p = 0.05) and within the subchondral bone plate (4.68 vs. 0.69 # / mm2; p \u3c 0.001). In addition to the classically-described turnover visible along trabecular surfaces, we also found visual evidence of intra-trabecular osteonal remodelling. In conclusion, this study shows significant alterations in bone turnover in both trabecular bone and within the subchondral bone plate at one-year post-ovariectomy. Remodelling of trabecular bone was due to both classically described hemi-osteonal and intra-trabecular osteonal remodelling. The presence of both localised osteopenia and accelerated bone remodelling within the medial tibial plateau provide a possible mechanism for subchondral microfractures in the aetiology of spontaneous osteonecrosis of the knee. Further utilisation of the ovariectomised ewe may be useful for further study in this field

Biomechanical comparison of the pullout properties of external skeletal fixation pins in the tibiae of intact and ovariectomised ewes.

The pin-bone interface is the least stable component of the external skeletal fixator. Concerns exist regarding the ability to obtain adequate implant purchase in poor quality bone. Consequently, reduced bone quality has been viewed as a contra-indication for the use of external skeletal fixators. The aim of this study was to investigate the holding power of two different fixator pin designs in bone from entire and ovariectomised sheep. Thirty-two aged ewes were divided into two groups. Group 1 were controls, and Group 2 were ovariectomised (OVX). The ewes were sacrificed 12 months post-ovariectomy and five pairs of tibiae were harvested from each group. The holding power of cortical and cancellous fixator pins was assessed at five standardised locations on each tibia. An increase in mean cortical thickness was noted in the OVX group. The holding power of cancellous fixator pins was superior to that of cortical pins, irrespective of whether or not ovariectomy had been performed. Cancellous pins had an increased holding power in post ovariectomy bone compared to control bone. Cortical pin performance was not affected by ovariectomy. There was a lack of correlation between the incidence of insertional fractures of the far cortex and implant holding power. The results raise questions over the effectiveness of ovariectomy in establishing osteopaenic bone suitable for assessing implant performance, hence further investigations are warranted

Serum IGF-1 is insufficient to restore skeletal size in the total absence of the growth hormone receptor

States of growth hormone (GH) resistance, such those observed in Laron dwarf patients, are characterized by mutations in the GH receptor (GHR), decreased serum and tissue IGF-1 levels, impaired glucose tolerance, and impaired skeletal acquisition. IGF-1 replacement therapy in such patients increases growth velocity but does not normalize growth. Herein we combined the GH-resistant (GHR knockout [GHRKO]) mouse model with mice expressing the hepatic Igf-1 transgene (HIT) to generate the GHRKO-HIT mouse model. In GHRKO-HIT mice, serum IGF-1 levels were restored via transgenic expression of Igf-1, allowing us to study how endocrine IGF-1 affects growth, metabolic homeostasis, and skeletal integrity. We show that in a GH-resistant state, normalization of serum IGF-1 improved body adiposity and restored glucose tolerance but was insufficient to support normal skeletal growth, resulting in an osteopenic skeletal phenotype. The inability of serum IGF-1 to restore skeletal integrity in the total absence of GHR likely resulted from reduced skeletal Igf-1 gene expression, blunted GH-mediated effects on the skeleton that are independent of serum or tissue IGF-1, and poor delivery of IGF-1 to the tissues. These findings are consistent with clinical data showing that IGF-I replacement therapy in patients with Laron syndrome does not achieve full skeletal growth.Fil: Wu, Yingjie. University Of New York; Estados UnidosFil: Sun, Hui. University Of New York; Estados UnidosFil: Basta Pljakic, Jelena. City College of New York; Estados UnidosFil: Cardoso, Luis. City College of New York; Estados UnidosFil: Kennedy, Oran D.. City College of New York; Estados UnidosFil: Jasper, Hector Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; ArgentinaFil: Domene, Horacio Mario. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; ArgentinaFil: Karabatas, Liliana Margarita. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; ArgentinaFil: Guida, María Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; ArgentinaFil: Schaffler, Mitchell B.. City College of New York; Estados UnidosFil: Rosen, Clifford J.. Maine Medical Center Research Institute; Estados UnidosFil: Yakar, Shoshana. University Of New York; Estados Unido

The Effect of Fluid Flow Shear Stress and Substrate Stiffness on Yes-Associated Protein (YAP) Activity and Osteogenesis in Murine Osteosarcoma Cells

Osteosarcoma (OS) is an aggressive bone cancer originating in the mesenchymal lineage. Prognosis for metastatic disease is poor, with a mortality rate of approximately 40%; OS is an aggressive disease for which new treatments are needed. All bone cells are sensitive to their mechanical/ physical surroundings and changes in these surroundings can affect their behavior. However, it is not well understood how OS cells specifically respond to fluid movement, or substrate stiffness—two stimuli of relevance in the tumor microenvironment. We used cells from spontaneous OS tumors in a mouse engineered to have a bone-specific knockout of pRb-1 and p53 in the osteoblast lineage. We silenced Sox2 (which regulates YAP) and tested the effect of fluid flow shear stress (FFSS) and substrate stiffness on YAP expression/activity—which was significantly reduced by loss of Sox2, but that effect was reversed by FFSS but not by substrate stiffness. Osteogenic gene expression was also reduced in the absence of Sox2 but again this was reversed by FFSS and remained largely unaffected by substrate stiffness. Thus we described the effect of two distinct stimuli on the mechanosensory and osteogenic profiles of OS cells. Taken together, these data suggest that modulation of fluid movement through, or stiffness levels within, OS tumors could represent a novel consideration in the development of new treatments to prevent their progression