Osteocytes Regulate Primary Lymphoid Organs and Fat Metabolism

Abstract

Osteocytes act as mechanosensors to control local bone volume. However, their roles in the homeostasis of remote organs are largely unknown. We show that ablation of osteocytes in mice (osteocyte-less [OL] mice) leads to severe lymphopenia, due to lack of lymphoid-supporting stroma in both the bone marrow and thymus, and complete loss of white adipose tissues. These effects were reversed when osteocytes were replenished within the bone. In contrast, neither in vivo supply of T cell progenitors and humoral factors via shared circulation with a normal parabiotic partner nor ablation of specific hypothalamic nuclei rescued thymic atrophy and fat loss in OL mice. Furthermore, ablation of the hypothalamus in OL mice led to hepatic steatosis, which was rescued by parabiosis with normal mice. Our results define a role for osteocytes as critical regulators of lymphopoiesis and fat metabolism and suggest that bone acts as a central regulator of multiple organs.

Regulation of hematopoiesis in endosteal microenvironments

“…These changes in hematopoietic cells under microgravity conditions are widely thought to be cell intrinsic. A recent study, however, showed that microgravity disrupts the osteocyte network accompanied with a reduction in B cells in the BM, and that the depletion of osteocytes leads to a decrease in B and T lymphocytes in the blood, due to the impaired development of stromal cells that support B cells in the BM and T cells in the thymus, respectively [14]. Moreover, recent studies have revealed that osteocytes embedded in the bone matrix have critical roles in regulating hematopoietic cells.…”

“…A number of important roles for osteocytes in bone biology, such as mechanosensation and mineral metabolism, have been identified in previous studies [11]. A series of recent studies, including one by our group, has revealed the importance of osteocytes in the regulation of hematopoiesis [12][13][14]. In this review, we provide an overview of advances in our knowledge of regulatory mechanisms in the hematopoietic system by osteolineage cells in the endosteal area.…”

Osteocytes and Homeostasis of Remote Organs

“…For example, osteocytes regulate osteoblasts to control not only bone remodeling but also the niche function of HSCs by receiving signals from the sympathetic nervous system (8). Furthermore, osteocytes regulate the microenvironment that supports lymph production by primary lymphoid organs, such as the BM and thymus, and fat metabolism throughout the body (9). In this article, we review the unique roles of bone-buried osteocytes as commanders of the HSC niche and regulators of multiple organs HSC niche inside bone First, the study of osteoblasts rather than osteocytes become a trigger for joint research of bone metabolism and hematopoiesis.…”

Communication of bone cells with hematopoiesis, immunity and energy metabolism

“…These results revealed that osteocytes maintained peripheral fat in cooperation with the central nervous system. 46 Thus, the bone tissue equipped with osteocytes orchestrates remote organs to maintain whole body homeostasis of immunity and fat metabolism ( Figure 3). Recently, osteocalcin produced by osteoblasts has been recognized as a critical homeostatic regulator of glucose metabolism by acting on pancreatic b cells and adipocytes.…”

“…41 Using the mouse tail suspension system, we confirmed that microgravity on the hind limbs disrupts osteocyte cellular network in the bone tissue and reduces the number of lymphocytes in the suspended BM. 46 To elucidate whether osteocytes were critical for homeostasis of the immune system and even other organs, we used OL mice that manifested osteoporosis with defective mechanotransduction. 41 Ablation of osteocytes led to severe lymphopenia due to the lack of lymphoid-supporting stroma in both the BM for B-cell precursors and the thymus for T-cell precursors, and a marked loss of white adipose tissues.…”