The evaluation of bone and mineral metabolism alterations in MMP13 KO lactating mice

• Grant number: 22/02978-7
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: September 01, 2022
• End date: August 31, 2023
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Francisco José Albuquerque de Paula
• Grantee: Maisa Monseff Rodrigues da Silva
• Supervisor: Roland Baron
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: Harvard University, Boston, United States
• Associated to the scholarship: 21/01475-9 - The relationship between bone, fat and muscle tissues in patients with X Linked Hypophosphatemic Rickets (XLHR), BP.DD

Abstract

Osteocytic osteolysis refers to the phenomenon of resorption of its surrounding perilacunar matrix by the osteocyte. The relevance of perilacunar matrix degradation (PLMD) recently started to be recognized and became known as an important step in bone remodeling, changing the understanding of bone physiology. It has been shown that modifications in perilacunar bone matrix and lacunar size can have an impact on fracture risk and bone quality. Both resorption and formation can occur on the lacunar wall, so it is now referred to as peri-lacunar remodeling (PLR). Further understanding of how PLR is controlled is fundamental for future interventions that can unfold into treatments for bone diseases. A model for the study of bone resorption physiology is lactation. The changes that take place to enrich the milk with calcium involve most importantly increased calcium intestinal absorption. There is however a 30% bone mass loss in mice, reversible after weaning, pointing to the importance of mobilizing calcium deposits. Bone loss and milk calcium enrichment were mostly attributed to osteoclast activity. However, the precise mechanisms regulating this process are not entirely elucidated, and it has been shown that in lactating mice, osteocyte lacunae are significantly enlarged compared with virgin mice. These are important clues regarding the contribution of osteocytes in bone remodeling and mineral homeostasis. Recent data shows that Ctsk deletion in osteocytes of lactating mice was capable of modifying the osteocyte lacunar area and preventing bone deterioration, as well as had endocrine repercussions, especially in the PTH-calcitriol axis. The osteocyte regulation of the PRL is modulated by an array of factors (hormones, cytokines, loading/unloading, and lactation), that has been investigated scarcely. Matrix degradation can hide a key link in the modulation of osteocytes, as growth factors and cytokines are part of the composition of peptides of the bone matrix. As osteocytes are the sensors of bone, PLMD can also influence osteoblast and osteoclast activity. At present, there is robust evidence showing the importance of the perilacunar osteolysis component in models of bone catabolism. In addition to cathepsin K, the osteocyte and the perilacunar matrix harbor other molecules whose biochemical role is still to be fully recognized. MMP13 encodes an enzyme known as collagenase 3, responsible for extracellular collagen degradation. When knocked out in mice, it leads to impaired endochondral ossification and increased trabecular bone volume at skeletal maturity. It can be hypothesized that osteocytes may produce key peptides capable of promoting PLMD and possibly activation of matrix-derived growth factors (MDGFs). Bone resorption releases MDGFs that have autocrine, paracrine, and endocrine actions, which determine the balance between bone anabolism and catabolism. The spatiotemporal release and activation of matrix TGF² during osteocytic osteolysis may be a key element of bone balance during lactation. The study was proposed to further elucidate the mechanisms that orchestrate the skeleton's normal physiology. We hypothesize that the knockout of MMP13 in lactating mice may impact bone mass through PLMD, and we will further investigate its role in mineral metabolism. We propose to investigate the role of PLMD (impaired by osteocyte target MMP13 deletion) in skeletal response during lactation in mice. The goal of our studies is to explore how the surrounding matrix and its modifications by osteocytes affect its biology, regulate bone remodeling, and how these changes affect the hormonal regulation of calcium during lactation. The area that we propose to investigate is, for the most part, unexplored and resides between two rapidly advancing areas of research. On one hand, we will explore the biological role of osteocytes in skeletal homeostasis and, on the other, osteocytic osteolysis and its role in calcium and phosphate homeostasis. (AU)