Inhibition of GSK-3β Rescues the Impairments in Bone Formation and Mechanical Properties Associated with Fracture Healing in Osteoblast Selective Connexin 43 Deficient Mice

Connexin 43 (Cx43) is the most abundant gap junction protein in bone and is required for osteoblastic differentiation and bone homeostasis. During fracture healing, Cx43 is abundantly expressed in osteoblasts and osteocytes, while Cx43 deficiency impairs bone formation and healing. In the present study we selectively deleted Cx43 in the osteoblastic lineage from immature osteoblasts through osteocytes and tested the hypothesis that Cx43 deficiency results in delayed osteoblastic differentiation and impaired restoration of biomechanical properties due to attenuated β-catenin expression relative to wild type littermates. Here we show that Cx43 deficiency results in alterations in the mineralization and remodeling phases of healing. In Cx43 deficient fractures the mineralization phase is marked by delayed expression of osteogenic genes. Additionally, the decrease in the RankL/ Opg ratio, osteoclast number and osteoclast size suggest decreased osteoclast bone resorption and remodeling. These changes in healing result in functional deficits as shown by a decrease in ultimate torque at failure. Consistent with these impairments in healing, β-catenin expression is attenuated in Cx43 deficient fractures at 14 and 21 days, while Sclerostin (Sost) expression, a negative regulator of bone formation is increased in Cx43cKO fractures at 21 days, as is GSK-3β, a key component of the β-catenin proteasomal degradation complex. Furthermore, we show that alterations in healing in Cx43 deficient fractures can be rescued by inhibiting GSK-3β activity using Lithium Chloride (LiCl). Treatment of Cx43 deficient mice with LiCl restores both normal bone formation and mechanical properties relative to LiCl treated WT fractures. This study suggests that Cx43 is a potential therapeutic target to enhance fracture healing and identifies a previously unknown role for Cx43 in regulating β-catenin expression and thus bone formation during fracture repair.     

Relationship of physical fitness, hormone replacement therapy, and hemostatic risk factors in postmenopausal women.

This cross-sectional study evaluated the relationship of physical fitness, hormone replacement therapy (HRT), and hemostatic profiles at rest and after an acute bout of maximal exercise in 48 healthy postmenopausal women. Subjects were categorized by fitness and HRT user status into four groups: unfit nonusers, fit nonusers, unfit users, and fit users. Fibrinolytic variables tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1) activity, and antigen and prothrombin fragment 1 + 2, a molecular marker of in vivo thrombin generation, were measured before and after maximal exercise. Fibrinogen was also measured at rest. Higher tPA and lower PAI-1 activities (P <0.05) were seen in HRT users and fit groups. tPA and PAI-1 antigens were lower in HRT and fit groups (P <0.05) but not after correction for body mass index. Prothrombin fragment 1 + 2 was lower in the fit groups regardless of HRT status (P <0.05). Fibrinogen was similar in all groups. Favorable hemostatic profiles were observed in physically fit compared with unfit women, especially in HRT nonusers. Thus fitness is more strongly related to these hemostatic risk factors compared with HRT since HRT did not affect these hemostatic variables in fit postmenopausal women.     

The new biology of ageing

Human life expectancy in developed countries has increased steadily for over 150 years, through improvements in public health and lifestyle. More people are hence living long enough to suffer age-related loss of function and disease, and there is a need to improve the health of older people. Ageing is a complex process of damage accumulation, and has been viewed as experimentally and medically intractable. This view has been reinforced by the realization that ageing is a disadvantageous trait that evolves as a side effect of mutation accumulation or a benefit to the young, because of the decline in the force of natural selection at later ages. However, important recent discoveries are that mutations in single genes can extend lifespan of laboratory model organisms and that the mechanisms involved are conserved across large evolutionary distances, including to mammals. These mutations keep the animals functional and pathology-free to later ages, and they can protect against specific ageing-related diseases, including neurodegenerative disease and cancer. Preliminary indications suggest that these new findings from the laboratory may well also apply to humans. Translating these discoveries into medical treatments poses new challenges, including changing clinical thinking towards broad-spectrum, preventative medicine and finding novel routes to drug development.     

Reproductive life history of ocelotsLeopardus pardalis in southern Texas

The ocelotLeopardus pardalis Linnaeus, 1758 is an endangered felid in the United States currently restricted to southern Texas. The objectives of our study were to obtain data on ocelot parturition dates, fecundity, sex ratios, den characteristics, and first year survival, all of which are critical in development of population viability models. Sixteen parturition events were recorded ranging from mid-April to late December for 12 wild ocelots. Cumulatively, litters consisted of 1 or 2 kittens (ˉ = 1.2 ± 0.44 SD). Cumulative sex ratio was 1∶2.5 (male:female); however, there was no significant difference between the observed sex ratio and a 1∶1 sex ratio. Ten den sites were in close proximity (≤ 10 m) to dense thornshrub. Adult female ocelots used 2 to 4 den sites for each litter with distance between consecutively occupied dens ranging from 110 to 280 m (ˉ = 158 m ± 93 SD). An estimated annual survival for ocelots 0 to 1 year of age was 0.68. Evidence suggests that ocelots in the wild may breed more frequently than had been previously hypothesized.     

Intestinal Coccidiosis in a Patient with Alpha-chain Disease

During an ultrastructural study of small-intestinal mucosa from a patient suffering from alpha-chain disease organisms were identified within the epithelial cytoplasm which showed the fine structural features of the coccidian group. Though coccidiosis is well recognized as causing a diarrhoeal and often lethal illness in animals it has been neglected as a cause of disease in man. Thus this finding may be significant and warrants further investigation into its possible role in the pathogenesis of alpha-chain disease.