Advanced bio-manufacturing: scaffold model for M leprae and bone disorder study

• Grant number: 23/00589-6
• Support Opportunities: Regular Research Grants
• Start date: May 01, 2023
• End date: April 30, 2025
• Field of knowledge: Engineering - Biomedical Engineering - Bioengineering
• Agreement: University of Manchester
• Mobility Program: SPRINT - Projetos de pesquisa - Mobilidade
• Principal Investigator: Marco Andrey Cipriani Frade
• Grantee: Marco Andrey Cipriani Frade
• Principal researcher abroad: Glen Cooper
• Institution abroad: University of Manchester, England
• Principal researcher abroad: Weiguang Wang
• Institution abroad: University of Manchester, England
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Guilherme Ferreira Caetano
• Associated research grant: 21/13429-1 - Clinical and serological screening for Leprosy by samples from the COVID-19 survey in Ribeirão Preto, AP.R

Abstract

Surprisingly leprosy still exists and affects around 200,000 people worldwide. Bone damage occurs in approximately 80% of leprosy patients, predominantly located at the hands, feet and face. Facial and acral skeletal deformities are historic hallmarks of leprosy. Mycobacterium leprae is the causative agent of leprosy, an obligate intracellular pathogen able to invade the peripheral nervous system, causing nerve damage, often leading to peripheral neuropathy. The interaction of M. leprae with peripheral nerves has been studied over the last decades and has resulted in the characterization of bacteria and their receptors involved with Schwann cells. In contrast, the mechanisms underlying leprosy-induced bone damage have not been thoroughly explored, which is a major clinical challenge. In the affected bones, M. leprae-filled macrophages can be observed in the medullar cavity and trabecular bone destruction. Signs of periostitis, different degrees of phalange resorption, bone cysts, trabeculation loss and osteoporosis is reported. This is because M. leprae invasion generates molecules which inhibit mineralization within the bone structure. The Zn-metalloendopeptidase phosphate-regulating gene with homologies to endopeptidase on the X chromosome (PHEX) is a key regulatory protein in hydroxyapatite formation and bone mineralization, once the protein binds in osteoblasts and matrix extracellular phosphoglycoprotein (MEPE), protecting it from hydrolysis by cathepsin B proteases. This protease, secreted by osteoblasts, is reported to be elevated in leprosy patients, leading bone damage, reaching to limb amputation, in some cases. It was reported the MEPE hydrolysis generates molecules which inhibit calcium oxalate crystallization and crystal growth on the extracellular matrix, as well as, were able to inhibit mineralization in osteoblast cultures. Culturing M. leprae in vitro in 2D and 3D (scaffolds) approaches could crucially contribute for understanding the affected bone remodelling mechanism. It was shown by the ex vivo model of human skin (hOSEC) the bacillus completely changes the immunology (expression of cytokines). (AU)