Effects of mechanobiological signaling in bone marrow on skeletal health

Abstract

Bone marrow is a cellular tissue that forms within the pore space and hollow diaphysis of bones. As a tissue, its primary function is to support the hematopoietic progenitor cells that maintain the populations of both erythroid and myeloid lineage cells in the bone marrow, making it an essential element of normal mammalian physiology. However, bone's primary function is load bearing, and deformations induced by external forces are transmitted to the encapsulated marrow. Understanding the effects of these mechanical inputs on marrow function and adaptation requires knowledge of the material behavior of the marrow at multiple scales, the loads that are applied, and the mechanobiology of the cells. This paper reviews the current state of knowledge of each of these factors. Characterization of the marrow mechanical environment and its role in skeletal health and other marrow functions remains incomplete, but research on the topic is increasing, driven by interest in skeletal adaptation and the mechanobiology of cancer metastasis.

The effect of marrow secretome and culture environment on the rate of metastatic breast cancer cell migration in two and three dimensions

“…Migration in porous scaffolds fabricated from hydrogels or natural matrices could provide an additional relevant model that captures important features of the marrow environment such as vasculature and collagen or perlecan fiber structures (Curtis et al, 2020a). Stiffer matrices increased MDA-MB-231 migration rates in highly porous scaffolds, but decreased migration rate when pores were smaller than 5 µm (Lang et al, 2015).…”

“…The marrow cells are believed to express chemoattractant molecules that recruit the cancer cells and provide a suitable niche for survival Paget, 1889). Immune cells, which make up approximately 40% of bone marrow (Zhao et al, 2012, Curtis 2020a, mediate tumor metastasis through inflammatory responses (Balkwill et al, 2005;DeNardo et al, 2008). At the same time, hematopoietic precursor cells in bone marrow prepare metastatic niches for tumor cell arrival (Kaplan et al, 2005), while blocking these cells inhibits tumor growth and angiogenesis (Lyden et al, 2001).…”

“…At the same time, hematopoietic precursor cells in bone marrow prepare metastatic niches for tumor cell arrival (Kaplan et al, 2005), while blocking these cells inhibits tumor growth and angiogenesis (Lyden et al, 2001). Adipocytes, which are a major component of bone marrow (Scheller et al, 2014, Curtis 2020a, lose their lipid content, become fibroblastic, and increase the invasiveness of tumor cells when co-cultured with tumor cells (Bochet et al, 2013;Dirat et al, 2011;Herroon et al, 2013;Nieman et al, 2013). Mesenchymal stem cells (MSCs) in the bone marrow's central sinus also interact with breast cancer cells to support tumor proliferation by releasing supportive growth factors and adhesion molecules that promote cancer cell survival (Chaturvedi et al, 2014;Karnoub et al, 2007;Patel et al, 2010).…”

“…It is crucial to understand how breast cancer cells migrate toward bone in a 3-D environment to mimic physiological conditions. Metastatic progression is accompanied by changes in the mechanical environment (Kumar and Weaver, 2009), and cancer cells that engraft in bone face a distinct environment with soft marrow interspersed between rigid bone struts (Curtis, 2020a). Substrate stiffness directly impacts cancer cell proliferation and migration in 2-D cell cultures.…”

“…Immune cells, which make up approximately 40% of bone marrow ( Zhao et al. , 2012 , Curtis et al. , 2020a ), mediate tumor metastasis through inflammatory responses ( Balkwill et al.…”