Objective： Our aim was to investigate clinical and laboratory characteristics of osteoarthritic patients who had amyloid deposition in their knee joints. Methods： Synovial membranes were obtained from 36 patients wi...Objective： Our aim was to investigate clinical and laboratory characteristics of osteoarthritic patients who had amyloid deposition in their knee joints. Methods： Synovial membranes were obtained from 36 patients with knee osteoarthritis （OA） who underwent joint replacement surgery. From this sample, the diagnosis of amyloid was deter- mined by Congo red staining, which demonstrated apple-green birefringence under a polarized microscope. All syn- ovial membranes were immunohistochemically characterized for the expressions of amyloid immunoglobulin light chain （AL-K and AL-,k）, serum amyloid-A （SAA）, amyloidogenic transthyretin （ATTR）, and amyloidogenic 152- microglobulin （A152M）. Matrix-assisted laser desorption-ionizaton/time of flight mass spectrometry （MALDI-TOF MS） was used to analyze transthyretin （TTR） isoforms in the serum of each patient. Results： Nine cases （25%） were found to be amyloid-positive. Immunohistochemicaliy, eight cases （88.9%） had ATTR deposition, and one sample （11.1%） was shown to be AL-K-positive. MALDI-TOF MS identified that the TTR in the serum of the patients was unmodified wild-type TTR, TTR-Cys-S-S-Cys, and TTR-Cys-S-S-CysGly. The age at surgery and the disease duration were sig- nificantly higher in the ATTR-positive group than in the ATTR-negative group. Knee score and function score were significantly lower in the ATTR-positive group than in the ATTR-negative group. Conclusions： Amyloid deposition in synovial membranes of OA patients was found to be ATTR and AL-K. TTR in the serum of the patients was unmodified wild-type TTR together with two isoforms. The high age at surgery, long disease duration, and a deteriorated knee function were associated with ATTR amyloid deposition in the osteoarthritic knee joints.展开更多
Transthyretin(TTR),a plasma protein with a tetramer structure,could form amyloid fibril associated with several human diseases through the dissociation of tetramer and the misfolding of monomer.These amyloidogenesis c...Transthyretin(TTR),a plasma protein with a tetramer structure,could form amyloid fibril associated with several human diseases through the dissociation of tetramer and the misfolding of monomer.These amyloidogenesis can be inhibited by small molecules which bind to the central channel of TTR.A number of small molecules like 2-arylbenzoxazoles(ABZ)analogues are proposed as promising therapeutic strategy to treat amyloidosis.In this work,comparative molecular field analysis(CoMFA)and comparative molecular similarity indices analysis(CoMSIA)three-dimensional quantitative structure-activity relationship(3D-QSAR)and docking studies were performed on series of 2-arylbenzoxazoles(ABZ)and linker-Y analogues to investigate the inhibitory activities of TTR amyloidogenesis at atomic level.Significant correlation coefficients for ABZ series(CoMFA,r2=0.877,q2=0.431;CoMSIA,r2=0.836,q2=0.447)and those for linker-Y series(CoMFA,r2=0.828,q2=0.522;CoMSIA,r2=0.800,q2=0.493)were obtained,and the generated models were validated using test sets.In addition,docking studies on 6 compounds binding to TTR were performed to analyze the forward or reverse binding mode and interactions between molecules and TTR.These results from 3D-QSAR and docking studies have great significance for designing novel TTR amyloidogenesis inhibitors in the future.展开更多
文摘Objective： Our aim was to investigate clinical and laboratory characteristics of osteoarthritic patients who had amyloid deposition in their knee joints. Methods： Synovial membranes were obtained from 36 patients with knee osteoarthritis （OA） who underwent joint replacement surgery. From this sample, the diagnosis of amyloid was deter- mined by Congo red staining, which demonstrated apple-green birefringence under a polarized microscope. All syn- ovial membranes were immunohistochemically characterized for the expressions of amyloid immunoglobulin light chain （AL-K and AL-,k）, serum amyloid-A （SAA）, amyloidogenic transthyretin （ATTR）, and amyloidogenic 152- microglobulin （A152M）. Matrix-assisted laser desorption-ionizaton/time of flight mass spectrometry （MALDI-TOF MS） was used to analyze transthyretin （TTR） isoforms in the serum of each patient. Results： Nine cases （25%） were found to be amyloid-positive. Immunohistochemicaliy, eight cases （88.9%） had ATTR deposition, and one sample （11.1%） was shown to be AL-K-positive. MALDI-TOF MS identified that the TTR in the serum of the patients was unmodified wild-type TTR, TTR-Cys-S-S-Cys, and TTR-Cys-S-S-CysGly. The age at surgery and the disease duration were sig- nificantly higher in the ATTR-positive group than in the ATTR-negative group. Knee score and function score were significantly lower in the ATTR-positive group than in the ATTR-negative group. Conclusions： Amyloid deposition in synovial membranes of OA patients was found to be ATTR and AL-K. TTR in the serum of the patients was unmodified wild-type TTR together with two isoforms. The high age at surgery, long disease duration, and a deteriorated knee function were associated with ATTR amyloid deposition in the osteoarthritic knee joints.
基金supported by the National Natural Science Foundation of China(21072018)the Fundamental Research Funds for the Central Universities(ZY1213)the Foundation of State Key Laboratory of Natural and Biomimetic Drugs(K20120202)
文摘Transthyretin(TTR),a plasma protein with a tetramer structure,could form amyloid fibril associated with several human diseases through the dissociation of tetramer and the misfolding of monomer.These amyloidogenesis can be inhibited by small molecules which bind to the central channel of TTR.A number of small molecules like 2-arylbenzoxazoles(ABZ)analogues are proposed as promising therapeutic strategy to treat amyloidosis.In this work,comparative molecular field analysis(CoMFA)and comparative molecular similarity indices analysis(CoMSIA)three-dimensional quantitative structure-activity relationship(3D-QSAR)and docking studies were performed on series of 2-arylbenzoxazoles(ABZ)and linker-Y analogues to investigate the inhibitory activities of TTR amyloidogenesis at atomic level.Significant correlation coefficients for ABZ series(CoMFA,r2=0.877,q2=0.431;CoMSIA,r2=0.836,q2=0.447)and those for linker-Y series(CoMFA,r2=0.828,q2=0.522;CoMSIA,r2=0.800,q2=0.493)were obtained,and the generated models were validated using test sets.In addition,docking studies on 6 compounds binding to TTR were performed to analyze the forward or reverse binding mode and interactions between molecules and TTR.These results from 3D-QSAR and docking studies have great significance for designing novel TTR amyloidogenesis inhibitors in the future.
