title: Downregulation of PHEX in multibacillary leprosy patients: observational cross-sectional study.
abstract: BACKGROUND
  Peripheral nerve injury and bone lesions, well known leprosy complications, lead to deformities and incapacities. The phosphate-regulating gene with homologies to endopeptidase on the X chromosome (PHEX) encodes a homonymous protein (PHEX) implicated in bone metabolism. PHEX/PHEX alterations may result in bone and cartilage lesions. PHEX expression is downregulated by intracellular Mycobacterium leprae (M. leprae) in cultures of human Schwann cells and osteoblasts. M. leprae in vivo effect on PHEX/PHEX is not known.
  
  
  METHODS
  Cross-sectional observational study of 36 leprosy patients (22 lepromatous and 14 borderline-tuberculoid) and 20 healthy volunteers (HV). The following tests were performed: PHEX flow cytometric analysis on blood mononuclear cells, cytokine production in culture supernatant, 25-hydroxyvitamin D (OHvitD) serum levels and (99m)Tc-MDP three-phase bone scintigraphy, radiography of upper and lower extremities and blood and urine biochemistry.
  
  
  RESULTS
  Significantly lower PHEX expression levels were observed in lepromatous patients than in the other groups (χ(2) = 16.554, p < 0.001 for lymphocytes and χ(2) = 13.933, p = 0.001 for monocytes). Low levels of 25-(OHvitD) were observed in HV (median = 23.0 ng/mL) and BT patients (median = 27.5 ng/mL) and normal serum levels were found in LL patients (median = 38.6 ng/mL). Inflammatory cytokines, such as TNF, a PHEX transcription repressor, were lower after stimulation with M. leprae in peripheral blood mononuclear cells from lepromatous in comparison to BT patients and HV (χ(2) = 10.820, p < 0.001).
  
  
  CONCLUSIONS
  Downregulation of PHEX may constitute an important early component of bone loss and joint damage in leprosy. The present results suggest a direct effect produced by M. leprae on the osteoarticular system that may use this mechanism.
authors.affiliation: Disciplina de Patologia Geral e Laboratório de Imunopatologia, Departamento de Patologia e Laboratórios, Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro (UERJ), Av Professor Manuel de Abreu 444, Vila Isabel, Rio de Janeiro, RJ, 20550-170, Brazil. sandraboica@gmail.com.
authors.forename: Sandra R Boiça
authors.initials: SR
authors.lastname: Silva
authors.affiliation: Laboratório de Hanseníase, Instituto Oswaldo Cruz (IOC) - Oswaldo Cruz Foundation (FIOCRUZ), Av. Brasil 4365, Manguinhos, Rio de Janeiro, RJ, 21040-360, Brazil. anemirx@gmail.com.
authors.forename: Ximena
authors.initials: X
authors.lastname: Illarramendi
authors.affiliation: Laboratório de Biologia Molecular de Parasitas e Vetores, Instituto Oswaldo Cruz (IOC) - Oswaldo Cruz Foundation (FIOCRUZ), Av. Brasil 4365, Manguinhos, Rio de Janeiro, RJ, 21040-360, Brazil. tempone@ioc.fiocruz.br.
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Tempone
authors.affiliation: Laboratório de Hanseníase, Instituto Oswaldo Cruz (IOC) - Oswaldo Cruz Foundation (FIOCRUZ), Av. Brasil 4365, Manguinhos, Rio de Janeiro, RJ, 21040-360, Brazil. peddro.henrique@gmail.com.
authors.forename: Pedro H L
authors.initials: PH
authors.lastname: Silva
authors.affiliation: Laboratório de Hanseníase, Instituto Oswaldo Cruz (IOC) - Oswaldo Cruz Foundation (FIOCRUZ), Av. Brasil 4365, Manguinhos, Rio de Janeiro, RJ, 21040-360, Brazil. neryjac@ioc.fiocruz.br.
authors.forename: José A C
authors.initials: JA
authors.lastname: Nery
authors.affiliation: Serviço de Medicina Nuclear, Departamento de Radiologia, Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro (UERJ), Av. Prof. Manuel de Abreu 444, Vila Isabel, Rio de Janeiro, RJ, 20550-170, Brazil. monteiroamv@gmail.com.
authors.forename: Alexandra M V
authors.initials: AM
authors.lastname: Monteiro
authors.affiliation: Laboratório de Microbiologia Celular, Instituto Oswaldo Cruz (IOC) - Oswaldo Cruz Foundation (FIOCRUZ), Av. Brasil 4365, Manguinhos, Rio de Janeiro, RJ, 21040-360, Brazil. cpessola@ioc.fiocruz.br.
authors.forename: Maria Cristina V
authors.initials: MC
authors.lastname: Pessolani
authors.affiliation: Serviço de Medicina Nuclear, Departamento de Radiologia, Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro (UERJ), Av. Prof. Manuel de Abreu 444, Vila Isabel, Rio de Janeiro, RJ, 20550-170, Brazil. boasquevisque@gmail.com.
authors.forename: Edson
authors.initials: E
authors.lastname: Boasquevisque
authors.affiliation: Laboratório de Hanseníase, Instituto Oswaldo Cruz (IOC) - Oswaldo Cruz Foundation (FIOCRUZ), Av. Brasil 4365, Manguinhos, Rio de Janeiro, RJ, 21040-360, Brazil. euzenir@ioc.fiocruz.br.
authors.forename: Euzenir N
authors.initials: EN
authors.lastname: Sarno
authors.affiliation: Laboratório de Microbiologia Celular, Instituto Oswaldo Cruz (IOC) - Oswaldo Cruz Foundation (FIOCRUZ), Av. Brasil 4365, Manguinhos, Rio de Janeiro, RJ, 21040-360, Brazil. gmbpereira@gmail.com.|Disciplina de Patologia Geral e Laboratório de Imunopatologia, Departamento de Patologia e Laboratórios, Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro (UERJ), Av Professor Manuel de Abreu 444, Vila Isabel, Rio de Janeiro, RJ, 20550-170, Brazil. gmbpereira@gmail.com.
authors.forename: Geraldo M B
authors.initials: GM
authors.lastname: Pereira
authors.affiliation: Laboratório de Hanseníase, Instituto Oswaldo Cruz (IOC) - Oswaldo Cruz Foundation (FIOCRUZ), Av. Brasil 4365, Manguinhos, Rio de Janeiro, RJ, 21040-360, Brazil. esquenazi.danuza@gmail.com.|Disciplina de Patologia Geral e Laboratório de Imunopatologia, Departamento de Patologia e Laboratórios, Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro (UERJ), Av Professor Manuel de Abreu 444, Vila Isabel, Rio de Janeiro, RJ, 20550-170, Brazil. esquenazi.danuza@gmail.com.
authors.forename: Danuza
authors.initials: D
authors.lastname: Esquenazi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001842:Bone and Bones / Q000382:microbiology; D002356:Cartilage / Q000382:microbiology; D003430:Cross-Sectional Studies; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D064368:Healthy Volunteers; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000382:microbiology; D015439:Leprosy, Borderline / Q000378:metabolism*; D056006:Leprosy, Multibacillary / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010006:Osteoblasts / Q000382:microbiology; D053402:PHEX Phosphate Regulating Neutral Endopeptidase / Q000378:metabolism*; D012583:Schwann Cells / Q000382:microbiology; D013669:Technetium Tc 99m Medronate; D055815:Young Adult
chemical_list: D016207:Cytokines; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506231:PHEX protein, human; D013669:Technetium Tc 99m Medronate