The roles of bone remodeling in normal hematopoiesis and age-related hematological malignancies

Abstract

Prior research establishing that bone interacts in coordination with the bone marrow microenvironment (BMME) to regulate hematopoietic homeostasis was largely based on analyses of individual bone-associated cell populations. Recent advances in intravital imaging has suggested that the expansion of hematopoietic stem cells (HSCs) and acute myeloid leukemia cells is restricted to bone marrow microdomains during a distinct stage of bone remodeling. These findings indicate that dynamic bone remodeling likely imposes additional heterogeneity within the BMME to yield differential clonal responses. A holistic understanding of the role of bone remodeling in regulating the stem cell niche and how these interactions are altered in age-related hematological malignancies will be critical to the development of novel interventions. To advance this understanding, herein, we provide a synopsis of the cellular and molecular constituents that participate in bone turnover and their known connections to the hematopoietic compartment. Specifically, we elaborate on the coupling between bone remodeling and the BMME in homeostasis and age-related hematological malignancies and after treatment with bone-targeting approaches. We then discuss unresolved questions and ambiguities that remain in the field.

Inflammation and aging: signaling pathways and intervention therapies

“…With age, red bone marrow is gradually replaced by fat cells, leading to yellow bone marrow formation that inhibits hematopoietic function. 105 The decreased secretion of nutrient factors by bone marrow stromal cells can result in an enhanced differentiation of HSCs into myeloid cells and a reduced differentiation into lymphocytes. This imbalance in myeloid/lymphoid differentiation is one of the manifestations of HSC aging.…”

“…This imbalance in myeloid/lymphoid differentiation is one of the manifestations of HSC aging. [105][106][107] Importantly, aged HSCs tend to differentiate more towards myeloid cells, while their ability to support lymphoid cell maturation decreases. This leads to a reduction in the number of precursors for T and B cells with increasing age.…”

Bone Marrow Adipose Tissue

“…BMAT secretes adipokines and growth factors, including adiponectin and leptin, which influence the fate and function of hematopoietic cells. Marrow adipocytes have been demonstrated to promote hematopoietic stem cell survival and support the regeneration of HSCs following irradiation or chemotherapy treatment through the secretion of stem cell factors [46,63].…”

The Ins and Outs of Endosteal Niche Disruption in the Bone Marrow: Relevance for Myeloma Oncogenesis

“…Many molecular and cellular factors are involved and have been reviewed elsewhere [15,16]. Importantly, age-related bone remodeling has effects on normal hematopoiesis because it affects the endosteal niche [17][18][19], which is a specialized microenvironment located in the bone marrow that plays a critical role in the regulation of hematopoietic stem cells (HSCs) [20,21]. The endosteal niche is located near the inner surface of the bone, where the presence of OB is thought to provide HSCs with signals that regulate their self-renewal and differentiation, ensuring that the bone marrow maintains a healthy and functional population of blood cells.…”

“…Thus, the skeletal bone aging clearly alters the BME. However, direct evidence of the direct correlations between the aged bone phenotype, niche alterations, and hematopoietic functions is still lacking [19].…”