Effects of local use of mesenchymal stem cells and systemic use of parathormone and pentoxifylline in bone defect repair

Author(s)

Jaqueline Isadora Reis Ramos

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Odontologia de Ribeirão Preto (PCARP/BC)
• Defense date: 2023-12-21

Examining board members

Adalberto Luiz Rosa; Emanuela Prado Ferraz; Gileade Pereira Freitas; Alexander Tadeu Sverzut

• Advisor: Adalberto Luiz Rosa; Márcio Mateus Beloti

Abstract

Bone tissue regeneration, in certain clinical situations, requires additional treatments, including cellular therapy, based on the local use of cells, and pharmacological therapy, based on the systemic use of drugs with an anabolic effect on the bone tissue. In cell therapy, mesenchymal stem cells (MSCs) have the potential to induce bone formation when locally injected into bone defects. However, they do not yet result in complete bone regeneration. In pharmacological therapy, two drugs are clinically available, parathormone (PTH) and pentoxifylline (PTX), both with an anabolic effect on bone tissue. In this context, the aim of this study was to evaluate whether the combination of local use of MSCs with the systemic use of PTH and PTX is capable of inducing bone defect repair. Firstly, through microtomography (µCT) and histological evaluation, we investigated the most effective doses of PTH (administered subcutaneously) and PTX (administered orally) on bone tissue after 28 days of daily use. To do this, we evaluated calvaria and femurs of rats. In the calvaria, 5mm bone defects were created and, to mimic a pre- existing bone defect, treatments were started only 2 weeks after the defects creation. The systemic effects of each of these drugs, as well as their combination, on body weight, blood count, serum calcium levels, bone formation (P1NP) and bone resorption (CTX) markers, and histological analysis of the kidneys and liver were evaluated. Bone formation in rat calvaria defects induced by the combination of local injection of MSCs (5.106 cells/50 µl of PBS) with systemic use of PTH, PTX or their combination was assessed weekly by µCT. Our results demonstrated that the most effective doses of PTH and PTX to induce bone formation were 40 µg/kg and 60 mg/kg, respectively. The use of PTH, PTX or their combination did not demonstrate any adverse systemic effects after 28 days of treatment. Although both drugs are safe and capable of inducing bone tissue formation, when combined with cellular therapy they do not present a synergistic effect, therefore, the combination of PTH, PTX and MSCs does not represent an adequate therapy to obtain the regeneration of bone defects. (AU)

• FAPESP's process: 20/03616-6 - Effect of local injection of mesenchymal stem cells combined with systemic injections of parathyroid hormone and pentoxifylline on bone repair
• Grantee: Jaqueline Isadora Reis Ramos
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)