Paget's disease of bone (PDB) is a common metabolic bone disease that is characterized by aberrant focal bone remodeling, which is caused by excessive osteoclastic bone resorption followed by disorganized osteoblastic bone formation. Genetic factors are a critical determinant of PDB pathogenesis, and several susceptibility genes and loci have been reported, including SQSTM1, TNFSF11A, TNFRSF11B, VCP, OPTN, CSF1 and DCSTAMP. Herein, we report a case of Chinese familial PDB without mutations in known genes and identify a novel c.163G>C (p.Val55Leu) mutation in FKBP5 (encodes FK506-binding protein 51, FKBP51) associated with PDB using whole-exome sequencing. Mutant FKBP51 enhanced the Akt phosphorylation and kinase activity in cells. A study of osteoclast function using FKBP51V55L KI transgenic mice proved that osteoclast precursors from FKBP51V55L mice were hyperresponsive to RANKL, and osteoclasts derived from FKBP51V55L mice displayed more intensive bone resorbing activity than did FKBP51WT controls. The osteoclast-specific molecules tartrate-resistant acid phosphatase, osteoclast-associated receptor and transcription factor NFATC1 were increased in bone marrow-derived monocyte/macrophage cells (BMMs) from FKBP51V55L mice during osteoclast differentiation. However, c-fos expression showed no significant difference in the wild-type and mutant groups. Akt phosphorylation in FKBP51V55L BMMs was elevated in response to RANKL. In contrast, IκB degradation, ERK phosphorylation and LC3II expression showed no difference in wild-type and mutant BMMs. Micro-CT analysis revealed an intensive trabecular bone resorption pattern in FKBP51V55L mice, and suspicious osteolytic bone lesions were noted in three-dimensional reconstruction of distal femurs from mutant mice. These results demonstrate that the mutant FKBP51V55L promotes osteoclastogenesis and function, which could subsequently participate in PDB development.
Acid Phosphatase ; Animals ; Asian Continental Ancestry Group ; Bone Diseases, Metabolic ; Bone Remodeling ; Bone Resorption ; Femur ; Humans ; Mice ; Mice, Transgenic ; Osteitis Deformans* ; Osteoblasts ; Osteoclasts ; Osteogenesis ; Phosphorylation ; Phosphotransferases ; Tacrolimus Binding Proteins ; Transcription Factors

ObjectiveTo explore the impact of blood-invigorating and stasis-dissolving medicinals combined with conventional western medicine on the major adverse cardiovascular events （MACE） in patients with coronary heart disease （CHD） after percutaneous coronary intervention （PCI）. MethodsA prospective cohort study was conducted to collect data on consecutive cases of CHD after PCI. According to whether blood-invigorating and stasis-dissolving medicinals were used， the cases were divided into a Chinese herbal medicinals （CHM） group and control group. The primary outcome was the incidence of MACE one year after PCI， while the secondary outcomes included TCM syndrome score and echocardiography left ventricular ejection fraction （LVEF）. Logistic regression analysis was performed to explore the influencing factors of MACE. ResultsA total of 844 patients who met the criteria were included， with 617 in the CHM group and 227 in the control group. The main blood-invigorating and stasis-dissolving medicinals being used were Danshen （Radix et Rhizoma Salviae Miltiorrhizae， 46.35%）， Chuanxiong （Rhizoma Chuanxiong， 45.87%）， and Chishao （Radix Paeoniae Rubra， 42.30%）. After a median follow-up of 12.73 months， the incidence of MACE in the CHM group （142/617， 23.01%） was significantly lower than that in the control group （68/227， 29.96%） with significant difference （OR=0.70， 95%CI 0.50 to 0.98， P = 0.04）. The LVEF of the CHM group ［（60.06±6.13）%］ was higher than that of the control group ［（58.27±7.36）%］ with significant difference （t = 0.356， P＜0.01）. The TCM syndrome score in the CHM group decreased to 12.66±4.47， while that in the control group increased to 13.81±3.88， with the results favoring the CHM group （t = 2.78， P＜0.01）. Univariate analysis showed correlations between the incidence of MACE after PCI and the use of blood-invigorating and stasis-dissolving medicinals， LVEF， usage of renin-angiotensin-aldosterone system （RAAS） inhibitors， TCM syndrome score， and usage of β blockers （P＜0.05）. Multivariate analysis showed that the use of blood-invigorating and stasis-dissolving medicinals was significantly associated with the reduction of MACE （P＜0.01）， while the baseline LVEF decline， TCM syndrome score increase， no use of RAAS inhibitors or β blockers were the risk factors of MACE after PCI （P＜0.05）. ConclusionThe use of blood-invigorating and stasis-dissolving medicinals based on the conventional western medicine can reduce the risk of MACE one year after PCI of CHD， improve the TCM syndromes and protect heart function.