Transcriptional reprogramming during human osteoclast differentiation identifies regulators of osteoclast activity

Enhanced osteoclastogenesis and osteoclast activity contribute to the development of osteoporosis,which is characterized by increased bone resorption and inadequate bone formation.As novel antiosteoporotic therapeutics are needed,understanding the genetic regulation of human osteoclastogenesis could help identify potential treatment targets.This study aimed to provide an overview of transcriptional reprogramming during human osteoclast differentiation.Osteoclasts were differentiated from CD14+monocytes from eight female donors.RNA sequencing during differentiation revealed 8980 differentially expressed genes grouped into eight temporal patterns conserved across donors.These patterns revealed distinct molecular functions associated with postmenopausal osteoporosis susceptibility genes based on RNA from iliac crest biopsies and bone mineral density SNPs.Network analyses revealed mutual dependencies between temporal expression patterns and provided insight into subtype-specific transcriptional networks.The donor-specific expression patterns revealed genes at the monocyte stage,such as filamin B(FLNB)and oxidized low-density lipoprotein receptor 1(OLR1,encoding LOX-1),that are predictive of the resorptive activity of mature osteoclasts.The expression of differentially expressed G-protein coupled receptors was strong during osteoclast differentiation,and these receptors are associated with bone mineral density SNPs,suggesting that they play a pivotal role in osteoclast differentiation and activity.The regulatory effects of three differentially expressed G-protein coupled receptors were exemplified by in vitro pharmacological modulation of complement 5 A receptor 1(C5AR1),somatostatin receptor 2(SSTR2),and free fatty acid receptor 4(FFAR4/GPR120).Activating C5AR1 enhanced osteoclast formation,while activating SSTR2 decreased the resorptive activity of mature osteoclasts,and activating FFAR4 decreased both the number and resorptive activity of mature osteoclasts.In conclusion,we report the occurrence of transcriptional reprogramming during human osteoclast differentiation and identified SSTR2 and FFAR4 as antiresorptive G-protein coupled receptors and FLNB and LOX-1 as potential molecular markers of osteoclast activity.These data can help future investigations identify molecular regulators of osteoclast differentiation and activity and provide the basis for novel antiosteoporotic targets.

Risk factors for long-term diabetic retinopathy in type 1 diabetes:evaluation of evidence from the Vascular Diabetic Complications in Southeast Sweden study

Diabetic retinopathy(DR)is by far the most common long-term complication in diabetes,and it is estimated that 95-97%of patients with type 1 diabetes will be affected in time(1,2).Given that blindness is expected to affect 3-8%of type 1 diabetes patients(3,4),it is vital to perform eye screening in order to treat sight-threatening complications prior to irreversible visual loss(5,6).

Ultra-wide field imaging in the screening of diabetic retinopathy

Despite recent advancements in care,diabetic retinopathy(DR)remains an important cause of blindness(1,2).Screening of DR has been introduced as part of the health care systems in various countries(3-5),and,consequently,recent data from UK have demonstrated that DR is no longer the leading cause of blindness in the working-age population(6).

Caffeine Increases VerticalJumping Height in Young Trained Males Before But Not After a Maximal Effort Strength Training Session

The aim of the present study was to investigate the effect of caffeine on vertical jumping height in rested condition and after a heavy strength training session.Six well-trained young males with experience in jump and strength training were included in this double-blinded,randomised study with cross-over design.Caffeine(3 mg/kg body weight)or placebo were ingested 45 min prior to the jump tests.Jumping was performed on a force platform and vertical jumping height was calculated.After a standardized warm up,participants performed jumping series consisting of three maximal jumps with 30 s rest between jumps followed by five maximal jumps with 7 s rest between jumps.The participants performed a heavy strength training of the leg muscles(leg press:3×15 reps)and the jumping series was repeated immediately after(30 s),and after 5 min and 15 min recovery.Caffeine increased the maximal vertical counter movement jump height(P≤0.05)and mean value of the 5-jump sequence prior to the strength training.Caffeine increased jump height by 2.2 cm±0.5 cm at the first jump.Blood lactate after the strength training increased to 6.97±1.20 and 7.77±0.54 mmol/L in PLA and CAF,respectively(P=0.19).The jump height was reduced by 8 cm after the strength training.There were no differences in jump height after ingestion of caffeine or placebo immediately after the strength training session or in the recovery period,but blood lactate in the recovery period was higher in CAF compared to PLA(ANOVA;P<0.05).Conclusion:Caffeine increased the vertical jump height in the resting state.However,after a maximal effort strength training session the positive effect of caffeine was no longer significant.