Ergonomic task reduction prevents bone osteopenia in a rat model of upper extremity overuse

Authors

Mary F Barbe, Nisha X Jain, Vicky S Massicote, Steven N Popoff, Ann E Barr-Gillespie

Abstract

We evaluated the effectiveness of ergonomic workload reduction of switching rats from a high repetition high force (HRHF) lever pulling task to a reduced force and reach rate task for preventing task-induced osteopenic changes in distal forelimb bones. Distal radius and ulna trabecular structure was examined in young adult rats performing one of three handle-pulling tasks for 12 weeks: 1) HRHF, 2) low repetition low force (LRLF); or 3) HRHF for 4 weeks and then LRLF thereafter (HRHF-to-LRLF). Results were compared to age-matched controls rats. Distal forelimb bones of 12-week HRHF rats showed increased trabecular resorption and decreased volume, as control rats. HRHF-to-LRLF rats had similar trabecular bone quality as control rats; and decreased bone resorption (decreased trabecular bone volume and serum CTX1), increased bone formation (increased mineral apposition, bone formation rate, and serum osteocalcin), and decreased osteoclasts and inflammatory cytokines, than HRHF rats. Thus, an ergonomic intervention of HRHF-to-LRLF prevented loss of trabecular bone volume occurring with prolonged performance of a repetitive upper extremity task. These findings support the idea of reduced workload as an effective approach to management of work-related musculoskeletal disorders, and begin to define reach rate and load level boundaries for such interventions.

Link To Article

http://dx.doi.org/10.2486/indhealth.2014-0159

Increased CCN2, substance P and tissue fibrosis are associated with sensorimotor declines in a rat model of repetitive overuse injury

Authors

Paul W. Fisher, Yingjie Zhao, Mario C. Rico, Vicky S. Massicotte, Christine K. Wade, Judith Litvin, Geoffrey M. Bove, Steven N. Popoff, Mary F. Barbe

Abstract

Key clinical features of cumulative trauma disorders include pain, muscle weakness, and tissue fibrosis, although the etiology is still under investigation. Here, we characterized the temporal pattern of altered sensorimotor behaviors and inflammatory and fibrogenic processes occurring in forearm muscles and serum of young adult, female rats performing an operant, high repetition high force (HRHF) reaching and grasping task for 6, 12, or 18 weeks. Palmar mechanical sensitivity, cold temperature avoidance and spontaneous behavioral changes increased, while grip strength declined, in 18-week HRHF rats, compared to controls. Flexor digitorum muscles had increased MCP-1 levels after training and increased TNFalpha in 6-week HRHF rats. Serum had increased IL-1beta, IL-10 and IP-10 after training. Yet both muscle and serum inflammation resolved by week 18. In contrast, IFNγ increased at week 18 in both muscle and serum. Given the anti-fibrotic role of IFNγ, and to identify a mechanism for the continued grip strength losses and behavioral sensitivities, we evaluated the fibrogenic proteins CCN2, collagen type I and TGFB1, as well as the nociceptive/fibrogenic peptide substance P. Each increased in and around flexor digitorum muscles and extracellular matrix in the mid-forearm, and in nerves of the forepaw at 18 weeks. CCN2 was also increased in serum at week 18. At a time when inflammation had subsided, increases in fibrogenic proteins correlated with sensorimotor declines. Thus, muscle and nerve fibrosis may be critical components of chronic work-related musculoskeletal disorders. CCN2 and substance P may serve as potential targets for therapeutic intervention, and CCN2 as a serum biomarker of fibrosis progression.

Link To Article

http://dx.doi.org/10.1007/s12079-015-0263-0  

Alcohol Alters the Activation of ERK1/2, a Functional Regulator of Binge Alcohol Drinking in Adult C57BL/6J Mice

Authors

Abigail E. Agoglia, Amanda C. Sharko, Kelly E. Psilos, Sarah E. Holstein, Grant T. Reid and Clyde W. Hodge

Abstract

Background Binge alcohol drinking is a particularly risky pattern of alcohol consumption that often precedes alcohol dependence and addiction. The transition from binge alcohol drinking to alcohol addiction likely involves mechanisms of synaptic plasticity and learning in the brain. The mitogen-activated protein kinase (MAPK) signaling cascades have been shown to be involved in learning and memory, as well as the response to drugs of abuse, but their role in binge alcohol drinking remains unclear. The present experiments were designed to determine the effects of acute alcohol on extracellular signaling-related kinases (ERK1/2) expression and activity and to determine whether ERK1/2 activity functionally regulates binge-like alcohol drinking.

Methods Adult male C57BL/6J mice were injected with ethanol (EtOH) (3.0 mg/kg, intraperitoneally) 10, 30, or 90 minutes prior to brain tissue collection. Next, mice that were brought to freely consume unsweetened EtOH in a binge-like access procedure were pretreated with the MEK1/2 inhibitor SL327 or the p38 MAPK inhibitor SB239063.

Results Acute EtOH increased pERK1/2 immunoreactivity relative to vehicle in brain regions known to be involved in drug reward and addiction, including the central amygdala and prefrontal cortex. However, EtOH decreased pERK1/2 immunoreactivity relative to vehicle in the nucleus accumbens core. SB239063 pretreatment significantly decreased EtOH consumption only at doses that also produced nonspecific locomotor effects. SL327 pretreatment significantly increased EtOH, but not sucrose, consumption without inducing generalized locomotor effects.

Conclusions These findings indicate that ERK1/2 MAPK signaling regulates binge-like alcohol drinking. As alcohol increased pERK1/2 immunoreactivity relative to vehicle in brain regions known to regulate drug self-administration, SL327 may have blocked this direct pharmacological effect of alcohol and thereby inhibited the termination of binge-like drinking.

Link To Article

http://dx.doi.org/10.1111/acer.12645

Cortical Bone Histomorphometry in Male Femoral Neck: The Investigation of Age-Association and Regional Differences

Authors

Xiaoyu Tong, Inari S. Burton, Hanna Isaksson, Jukka S. Jurvelin, Heikki Kröger

Abstract

Low bone volume and changes in bone quality or microarchitecture may predispose individuals to fragility fractures. As the dominant component of the human skeleton, cortical bone plays a key role in protecting bones from fracture. However, histological investigations of the underlying structural changes, which might predispose to fracture, have been largely limited to the cancellous bone. The aim of this study was to investigate the age-association and regional differences of histomorphometric properties in the femoral neck cortical bone. Undecalcified histological sections of the femoral neck (n = 20, aged 18–82 years, males) were cut (15 μm) and stained using modified Masson-Goldner stain. Complete femoral neck images were scanned, and cortical bone boundaries were defined using our previously established method. Cortical bone histomorphometry was performed with low (×50) and high magnification (×100). Most parameters related to cortical width (Mean Ct.Wi, Inferior Ct.Wi, Superior Ct.Wi) were negatively associated with age both before and after adjustment for height. The inferior cortex was the thickest (P < 0.001) and the superior cortex was the thinnest (P < 0.008) of all cortical regions. Both osteonal size and pores area were negatively associated with age. Osteonal area and number were higher in the antero-inferior area (P < 0.002) and infero-posterior area (P = 0.002) compared to the postero-superior area. The Haversian canal area was higher in the infero-posterior area compared to the postero-superior area (P = 0.002). Moreover, porosity was higher in the antero-superior area (P < 0.002), supero-anterior area (P < 0.002) and supero-posterior area (P < 0.002) compared to the infero-anterior area. Eroded endocortical perimeter (E.Pm/Ec.Pm) correlated positively with superior cortical width. This study describes the changes in cortical bone during ageing in healthy males. Further studies are needed to investigate whether these changes explain the increased susceptibility to femoral neck fractures.

Link To Article

http://dx.doi.org/10.1007/s00223-015-9957-9

Pharmacological inhibition of ​Dock5 prevents osteolysis by affecting osteoclast podosome organization while preserving bone formation

Authors

Virginie Vives, Gaëlle Cres, Christian Richard, Muriel Busson, Yann Ferrandez, Anne-Gaelle Planson, Mahel Zeghouf, Jacqueline Cherfils, Luc Malaval & Anne Blangy

Abstract

Osteoporosis is caused by excessive activity of bone-degrading osteoclasts over bone-forming osteoblast. Standard antiosteolytic treatments inhibit bone resorption by inducing osteoclast loss, with the adverse effect of hindering also bone formation. Formation of the osteoclast sealing zone requires ock5, a guanine nucleotide exchange factor for the small GTPase Rac, and 21, a chemical inhibitor of ock5, decreases bone resorption by cultured osteoclasts. Here we show that 21 directly inhibits the exchange activity of ock5 and disrupts osteoclast podosome organization. Remarkably, 21 administration protects mice against bone degradation in models recapitulating major osteolytic diseases: menopause, rheumatoid arthritis and bone metastasis. Furthermore, 21 administration does not affect bone formation and is not toxic. Our results validate the pharmacological inhibition of ock5 as a novel therapeutic route for fighting osteolytic diseases while preserving bone formation.

Link To Article

http://dx.doi.org/10.1038/ncomms7218