Downregulation of PHEX in multibacillary leprosy patients: observational cross-sectional study

Abstract

BackgroundPeripheral 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.MethodsCross-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 99mTc-MDP three-phase bone scintigraphy, radiography of upper and lower extremities and blood and urine biochemistry.ResultsSignificantly lower PHEX expression levels were observed in lepromatous patients than in the other groups (χ2 = 16.554, p < 0.001 for lymphocytes and χ2 = 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 (χ2 = 10.820, p < 0.001).ConclusionDownregulation 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0651-5) contains supplementary material, which is available to authorized users.

Presence of Senescent and Memory CD8+ Leukocytes as Immunocenescence Markers in Skin Lesions of Elderly Leprosy Patients

“…Leprosy is a neglected chronic infectious disease caused by Mycobacterium leprae , which remains a public health problem in low-income countries ( 1 , 2 ). M. leprae affects mainly the skin and peripheral nervous system, where the bacilli are responsible for neurological damage, bone resorption, and irreversible physical disabilities ( 3 – 5 ). Genetic and environmental factors contribute to disease progression ( 3 ).…”

Lepromatous Leprosy and Charcot Neuroarthropathy of Insensate Feet: A Case Report

“…This osteolysis and inflammation sometimes result in a characteristic plantar shift of the mid-pedal bones, often referred to as "rocker-bottom foot," as well as other physical distortions [ 11 ]. This effect may be further exacerbated by the potential osteolytic action of the M. leprae bacteria, which is hypothesized to result from the downregulation of the phosphate-regulating gene with homologies to endopeptidase on the X chromosome ( PHEX ), a gene with modulatory effects on bone matrix mineralization, phosphate renal excretion, serum levels of fibroblast growth factor 23 (FGF23) and 1,25(OH)2 vitamin D regulation [ 12 ].…”

Shedding Light on the Complex Regulation of FGF23

“…Mutations in either PHEX (XLH, X-linked hypophosphatemic rickets) and DMP1 (ARHR, autosomal recessive hypophosphatemic rickets) cause renal phosphate wasting and its clinical sequelae by primary elevations of FGF23. There are no descriptions in the literature of acquired malfunction or suppression of the PHEX protein, with the possible exception of a report on a patient with leprosy [ 58 ]. For DMP1, however, diseases that induce acquired suppression appear to exist.…”