Pathogenetic Study Of Mimic Juvenile Idiopathic Arthritis And Genetic Study Of Postmenopausal Osteoporosis

Objective: The aims of the study were: 1)The proband,a 21-year-old male,came to our department for suffering from "paroxysmal pain and swelling of finger and toe joints since his was four".The objective of this study was to clarify the diagnosis,the virulence gene and the pathogenesis of the disease.2)To determine the associations between polymorphisms of bone morphogenetic protein 7(BMP7)gene,serum cathepsin K and CTSK gene and bone mineral density(BMD),bone turnover markers and osteoporotic fracture in postmenopausal Chinese women.3)To investigate the effect of calcium and cholecalciferol or calcitriol supplementation on bone turnover marker levels,muscle strength and quality of life in postmenopausal Chinese women.Methods: 1)Firstly,we described the clinical manifestations,the laboratory tests results and the imaging examination of the affected 5 numbers of the family.The diagnosis was made by referring to wildly literature review and the information from OMIM database.Secondly,exome sequencing,mapping and haplotype analysis were used to identify the virulence gene in the patients,and Sanger sequencing was used to test the suspect genes in all family numbers and 250 healthy controls for confirmation.Finally,the Stat1 knockout and Stat1Y33 X knockin mouse model were used to explore the pathogenic mechanism of the disease.2)A total of 3815 independent healthy postmenopausal Chinese women including 1238 with osteoporotic fracture and 2577 controls were included.The BMD of the lumbar spine 1-4(L1-4)and proximal femur including femoral neck and total hip were measured by dual-energy X-ray absorptiometry(DXA).Eight tagging SNPs of BMP7 gene were genotyped simultaneously.Besideds,a cross-sectional study was conducted with 1752 postmenopausal Chinese women.Four tagging SNPs of the CTSK gene were genotyped.Serum cathepsin K and bone metabolism markers including serum intact PTH,25-hydroxyvitamin D [25(OH)D],?-Cross Laps of type I collagen containing cross-linked C-telopeptide(?-CTX)and procollagen type 1 N-terminal propeptide(P1NP)were measured.3)We conducted an open-labeled,2-year prospective,community-based trial in Shanghai.A total of 485 healthy postmenopausal women(63.44±5.04 years)from communities were separated into 3 groups and supplemented with: A)calcium(600 mg/d)only;B)calcium and cholecalciferol(800 IU/d);and C)calcium and calcitriol(0.25 ?g/d)for two years.Assessments including the serum levels of 25-hydroxyvitamin D [25(OH)D],PTH and beta C-terminal cross-linked telopeptide of type I collagen(?-CTX),amino-terminal propeptide of type I collagen(P1NP),osteocalcin(OC),muscle strength and quality of life at baseline,12-month and 24-month follow-ups.Results: 1)All the patients in the family shared the similar clinical manifestation.The proband showed swelling and deformed fingers and toes.The imaging studies revealed normal finger and toe articular structure accompanied by surrounded soft tissue swelling.The immunologic index were normal.We diagnosed the newly-found syndrome "mimic juvenile idiopathic arthritis".The determined virulence gene of this autosomal dominant syndrome was STAT1,which contained an heterozygous missense mutation in exon 3,c.99C>A(p.Y33X).We have not found the similar phenotype as the patients in the mouse model yet.2)After adjusting age,height and weight,there was no significant association between the 8 SNPs,9 haplotypes of BMP7 and BMD or osteoporotic fracture in postmenopausal Chinese women.No significant relationship was detected between serum cathepsin K and age,BMI,BMD or bone metabolic markers after adjustment for age and BMI.We failed to identify any significant association between the genotypes or haplotypes of CTSK and BMD,bone turnover markers,or serum cathepsin K.3)461 participants completed this study.The serum ?-CTX level in group A significantly increased at the 24-month follow-up compared with that at baseline,whereas serum ?-CTX in group C decreased significantly,accompanied by significant reduction in P1 NP and PTH levels.The grip strength of group C was maintained at the baseline level,but that of groups A and B strikingly decreased.The life quality of groups B and C remained consistent,whereas that of group A was significantly reduced at the 24-month follow-up.Conclusions: 1)In this study,we found a new disease in a non-consanguineous family.The disease was named "mimic juvenile idiopathic arthritis" and characterized with early-onset pain of swelling fingers and toes and normal immunologic index.STAT1 gene with Y33 X mutation was the virulence gene for this autosomal dominant syndrome.There was no similar phenotype as the patients found in the mouse model yet.2)Our findings suggested that the common genetic polymorphisms of BMP7,CTSK gene and serum cathepsin K are not major contributors to the variations in BMD,osteoporotic fracture or bone turnover markers in postmenopausal Chinese women.3)Supplementation with calcitriol and calcium modified the bone turnover marker levels and maintained muscle strength in postmenopausal women at the 24-month follow-up.Both cholecalciferol and calcitriol in combination with calcium prevented the aging-mediated decrease in the quality of life.