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Key Points The bone marrow niche supports the integration of two major organ systems — the skeleton and the marrow The niche is a unique microenvironment that is crucial for haematopoietic stem cell quiescence Important features of the niche include its cellular components, hypoxia, extracellular matrices, cytokines and growth factors, and vascularization Multiple myeloma and other cancer cells hijack and alter the bone marrow niche, and are altered by the niche in turn; thus, targeting niche–cancer interactions is a promising therapeutic avenue Novel in vitro and in vivo models of the bone marrow niche and cancer cells enable us to better understand interactions between cancer and bone marrow niche cells A more complete understanding of the biology of the unique bone marrow microenvironment must remain a major research priority The bone marrow niche is a unique microenvironment that integrates the physiology of the skeleton and the marrow to maintain the haematopoietic stem cell pool and support whole-organism homeostasis. Reagan and Rosen examine the features of this microenvironment and the consequences of its disruption, particularly in relation to invasion by cancer cells, and discuss how better understanding of the niche could inform treatments for various disorders including skeletal diseases and malignancies. The bone marrow niche consists of stem and progenitor cells destined to become mature cells such as haematopoietic elements, osteoblasts or adipocytes. Marrow cells, influenced by endocrine, paracrine and autocrine factors, ultimately function as a unit to regulate bone remodelling and haematopoiesis. Current evidence highlights that the bone marrow niche is not merely an anatomic compartment; rather, it integrates the physiology of two distinct organ systems, the skeleton and the marrow. The niche has a hypoxic microenvironment that maintains quiescent haematopoietic stem cells (HSCs) and supports glycolytic metabolism. In response to biochemical cues and under the influence of neural, hormonal, and biochemical factors, marrow stromal elements, such as mesenchymal stromal cells (MSCs), differentiate into mature, functioning cells. However, disruption of the niche can affect cellular differentiation, resulting in disorders ranging from osteoporosis to malignancy. In this Review, we propose that the niche reflects the vitality of two tissues — bone and blood — by providing a unique environment for stem and stromal cells to flourish while simultaneously preventing disproportionate proliferation, malignant transformation or loss of the multipotent progenitors required for healing, functional immunity and growth throughout an organism's lifetime. Through a fuller understanding of the complexity of the niche in physiologic and pathologic states, the successful development of more-effective therapeutic approaches to target the niche and its cellular components for the treatment of rheumatic, endocrine, neoplastic and metabolic diseases becomes achievable.

Menopause is associated with bone loss and enhanced visceral adiposity. A polyclonal antibody that targets the β-subunit of the pituitary hormone follicle-stimulating hormone (Fsh) increases bone mass in mice. Here, we report that this antibody sharply reduces adipose tissue in wild-type mice, phenocopying genetic haploinsufficiency for the Fsh receptor gene Fshr . The antibody also causes profound beiging, increases cellular mitochondrial density, activates brown adipose tissue and enhances thermogenesis. These actions result from the specific binding of the antibody to the β-subunit of Fsh to block its action. Our studies uncover opportunities for simultaneously treating obesity and osteoporosis. An antibody against the pituitary hormone Fsh reduces adiposity and increases thermogenesis in ovariectomized mice or mice fed a high-fat diet. Fat-reducing antibody Menopause is associated with bone loss and enhanced build-up of abdominal fat. Previously, Mone Zaidi and colleagues showed that an antibody against the pituitary hormone Fsh increases bone mass in mice. In this paper, they show that this antibody also reduces fatty tissue in mice that have had their ovaries removed or mice on a high fat diet. The anti-obesity effect is accompanied by increases in UCP1 expression and thermogenesis in brown and beige fat, increased whole-body oxygen consumption rate and physical activity. The authors suggest that these findings could open up opportunities for combined treatment of obesity and osteoporosis.

Bone is a favorable microenvironment for tumor growth and a frequent destination for metastatic cancer cells. Targeting cancers within the bone marrow remains a crucial oncologic challenge due to issues of drug availability and microenvironment-induced resistance. Herein, we engineered bone-homing polymeric nanoparticles (NPs) for spatiotemporally controlled delivery of therapeutics to bone, which diminish off-target effects and increase local drug concentrations. The NPs consist of poly(d , l -lactic-co-glycolic acid) (PLGA), polyethylene glycol (PEG), and bisphosphonate (or alendronate, a targeting ligand). The engineered NPs were formulated by blending varying ratios of the synthesized polymers: PLGA- b -PEG and alendronate-conjugated polymer PLGA- b -PEG-Ald, which ensured long circulation and targeting capabilities, respectively. The bone-binding ability of Ald-PEG-PLGA NPs was investigated by hydroxyapatite binding assays and ex vivo imaging of adherence to bone fragments. In vivo biodistribution of fluorescently labeled NPs showed higher retention, accumulation, and bone homing of targeted Ald-PEG-PLGA NPs, compared with nontargeted PEG-PLGA NPs. A library of bortezomib-loaded NPs (bone-targeted Ald-Bort-NPs and nontargeted Bort-NPs) were developed and screened for optimal physiochemical properties, drug loading, and release profiles. Ald-Bort-NPs were tested for efficacy in mouse models of multiple myeloma (MM). Results demonstrated significantly enhanced survival and decreased tumor burden in mice pretreated with Ald-Bort-NPs versus Ald-Empty-NPs (no drug) or the free drug. We also observed that bortezomib, as a pretreatment regimen, modified the bone microenvironment and enhanced bone strength and volume. Our findings suggest that NP-based anticancer therapies with bone-targeting specificity comprise a clinically relevant method of drug delivery that can inhibit tumor progression in MM.

Trpm8 (transient receptor potential cation channel, subfamily M, member 8) is expressed by sensory neurons and is involved in the detection of environmental cold temperatures. TRPM8 activity triggers an increase in uncoupling protein 1 ( Ucp1 )-dependent brown adipose tissue (BAT) thermogenesis. Bone density and marrow adipose tissue are both influenced by rodent housing temperature and brown adipose tissue, but it is unknown if TRPM8 is involved in the co-regulation of thermogenesis and bone homeostasis. To address this, we examined the bone phenotypes of one-year-old Trpm8 knockout mice ( Trpm8-KO ) after a 4-week cold temperature challenge. Male Trpm8-KO mice had lower bone mineral density than WT, with smaller bone size (femur length and cross-sectional area) being the most striking finding, and exhibited a delayed cold acclimation with increased BAT expression of Dio2 and Cidea compared to WT. In contrast to males, female Trpm8-KO mice had low vertebral bone microarchitectural parameters, but no genotype-specific alterations in body temperature. Interestingly, Trpm8 was not required for cold-induced trabecular bone loss in either sex, but bone marrow adipose tissue in females was significantly suppressed by Trpm8 deletion. In summary, we identified sex differences in the role of TRPM8 in maintaining body temperature, bone microarchitecture and marrow adipose tissue. Identifying mechanisms through which cold temperature and BAT influence bone could help to ameliorate potential bone side effects of obesity treatments designed to stimulate thermogenesis.

Myeloma bone disease is a devastating complication of multiple myeloma (MM) and is caused by dysregulation of bone remodeling processes in the bone marrow microenvironment. Previous studies showed that microRNA-138 (miR-138) is a negative regulator of osteogenic differentiation of mesenchymal stromal cells (MSCs) and that inhibiting its function enhances bone formation in vitro. In this study, we explored the role of miR-138 in myeloma bone disease and evaluated the potential of systemically delivered locked nucleic acid (LNA)-modified anti-miR-138 oligonucleotides in suppressing myeloma bone disease. We showed that expression of miR-138 was significantly increased in MSCs from MM patients (MM-MSCs) and myeloma cells compared to those from healthy subjects. Furthermore, inhibition of miR-138 resulted in enhanced osteogenic differentiation of MM-MSCs in vitro and increased the number of endosteal osteoblastic lineage cells (OBCs) and bone formation rate in mouse models of myeloma bone disease. RNA sequencing of the OBCs identified TRPS1 and SULF2 as potential miR-138 targets that were de-repressed in anti-miR-138-treated mice. In summary, these data indicate that inhibition of miR-138 enhances bone formation in MM and that pharmacological inhibition of miR-138 could represent a new therapeutic strategy for treatment of myeloma bone disease.

Multiple myeloma (MM) is an incurable cancer of plasma cells with a 5‐year survival rate of 59%. Dysregulation of fatty acid (FA) metabolism is associated with MM development and progression; however, the underlying mechanisms remain unclear. Herein, we explore the roles of long‐chain fatty acid coenzyme A ligase (ACSL) family members in MM. ACSLs convert free long‐chain fatty acids into fatty acyl‐CoA esters and play key roles in catabolic and anabolic fatty acid metabolism. Analysis of the Multiple Myeloma Research Foundation (MMRF) CoMMpassSM study showed that high ACSL1 and ACSL4 expression in myeloma cells are both associated with worse clinical outcomes for MM patients. Cancer Dependency Map (DepMap) data showed that all five ACSLs have negative Chronos scores, and ACSL3 and ACSL4 were among the top 25% Hallmark Fatty Acid Metabolism genes that support myeloma cell line fitness. Inhibition of ACSLs in myeloma cell lines in vitro, using the pharmacological inhibitor Triacsin C (TriC), increased apoptosis, decreased proliferation, and decreased cell viability, in a dose‐ and time‐dependent manner. RNA‐sequencing analysis of MM.1S cells treated with TriC showed a significant enrichment in apoptosis, ferroptosis, and endoplasmic reticulum (ER) stress, and proteomic analysis of these cells revealed enriched pathways for mitochondrial dysfunction and oxidative phosphorylation. TriC also rewired mitochondrial metabolism by decreasing mitochondrial membrane potential, increasing mitochondrial superoxide levels, decreasing mitochondrial ATP production rates, and impairing cellular respiration. Overall, our data support the hypothesis that suppression of ACSLs in myeloma cells is a novel metabolic target in MM that inhibits their viability, implicating this family as a promising therapeutic target in treating myeloma. Triacsin C inhibition of the acyl‐CoA synthetase long chain (ACSL) family decreases multiple myeloma cell survival, proliferation, mitochondrial respiration, and membrane potential. Made with Biorender.com.

About the Authors: Pamela K. Kreeger * E-mail: kreeger@wisc.edu Affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin, United States of America ORCID logo https://orcid.org/0000-0001-8193-1007 Amy Brock Affiliation: Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas, United States of America ORCID logo https://orcid.org/0000-0001-8255-9024 Holly C. Gibbs Affiliation: Microscopy and Imaging Center, Texas A&M University, College Station, Texas, United States of America K. Jane Grande-Allen Affiliation: Department of Bioengineering, Rice University, Houston, Texas, United States of America Alice H. Huang Affiliation: Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America ORCID logo https://orcid.org/0000-0002-5037-6829 Kristyn S. Masters Affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin, United States of America ORCID logo https://orcid.org/0000-0001-6911-3116 Padmini Rangamani Affiliation: Department of Mechanical and Aerospace Engineering, University of California San Diego, San Diego, California, United States of America ORCID logo https://orcid.org/0000-0001-5953-4347 Michaela R. Reagan Affiliation: Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine, United States of America Shannon L. Servoss Affiliation: Ralph E. Martin Department of Chemical Engineering, University of Arkansas, Fayetteville, Arkansas, United States of America Introduction In the spring of 2020, nearly all academic institutions went to some level of shutdown/quarantine in order to slow the spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus that causes Coronavirus Disease 2019 (COVID-19). Consistent with this, some of the authors experienced or observed messaging from department chairs, center leaders, or mentors telling principal investigators (PIs) that the pandemic situation has likely created “extra time” for them to focus on writing grants and developing new ideas. Discussions of these data have focused primarily on the fact that women do a disproportionate amount of house and childcare [5–7], and options used to provide support for this unpaid work have essentially evaporated (e.g., limiting outside workers into the home for cleaning, day cares not accessible to children of nonessential workers, and school and summer camp closures). [...]the term “staff” refers to administrative staff, whether in support of the research or teaching missions of the university.

Multiple myeloma (MM) accounts for 13% to 15% of all blood cancers1 and is characterized by the proliferation of malignant cells within the bone marrow (BM). Despite important advances in treatment, most patients become refractory and relapse with the disease. As MM tumors grow in the BM, they disrupt hematopoiesis, create monoclonal protein spikes in the blood, initiate systemic organ and immune system shutdown,2 and induce painful osteolytic lesions caused by overactive osteoclasts and inhibited osteoblasts.3, 4 MM cells are also extremely dependent on the BM niche, and targeting the BM niche has been clinically transformative for inhibiting the positive-feedback \"vicious cycle\" between MM cells and osteoclasts that leads to bone resorption and tumor proliferation.5, 6, 7, 8 Bone marrow adipocytes (BMAs) are dynamic, secretory cells that have complex effects on osteoblasts and tumor cells, but their role in modifying the MM cell phenotype is relatively unexplored.9, 10, 11, 12, 13 Given their active endocrine function, capacity for direct cell-cell communication, correlation with aging and obesity (both MM risk factors), potential roles in bone disease, and physical proximity to MM cells, it appears that BMAs support MM cells.14, 15, 16, 17 This supposition is based on research from many laboratories, including our own. Therapeutically targeting the BMA may prove to be equally transformative in the clinic if the pathways through which BMAs affect MM cells can be determined. In this review, we discuss the potential for BMAs to provide free fatty acids to myeloma cells to support their growth and evolution. We highlight certain proteins in MM cells responsible for fatty acid uptake and oxidation and discuss the potential for therapeutically targeting fatty acid metabolism or BMAs from where they may be derived. © 2019 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Over the past century, the study of biological processes in the human body has progressed from tissue culture on glass plates to complex 3D models of tissues, organs, and body systems. These dynamic 3D systems have allowed for more accurate recapitulation of human physiology and pathology, which has yielded a platform for disease study with a greater capacity to understand pathophysiology and to assess pharmaceutical treatments. Specifically, by increasing the accuracy with which the microenvironments of disease processes are modeled, the clinical manifestation of disease has been more accurately reproduced in vitro. The application of these models is crucial in all realms of medicine, but they find particular utility in diseases related to the complex bone marrow niche. Osteoblast, osteoclasts, bone marrow adipocytes, mesenchymal stem cells, and red and white blood cells represent some of cells that call the bone marrow microenvironment home. During states of malignant marrow disease, neoplastic cells migrate to and join this niche. These cancer cells both exploit and alter the niche to their benefit and to the patient's detriment. Malignant disease of the bone marrow, both primary and secondary, is a significant cause of morbidity and mortality today. Innovative study methods are necessary to improve patient outcomes. In this review, we discuss the evolution of 3D models and compare them to the preceding 2D models. With a specific focus on malignant bone marrow disease, we examine 3D models currently in use, their observed efficacy, and their potential in developing improved treatments and eventual cures. Finally, we comment on the aspects of 3D models that must be critically examined as systems continue to be optimized so that they can exert greater clinical impact in the future. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Summary Multiple myeloma is an incurable cancer of the bone marrow that is dependent on its microenvironment, including bone marrow adipocytes (BMAds). Here, we discuss our findings that the reciprocal interaction of myeloma cells and BMAds, leads to myeloma cell survival and induces metabolic dysfunction and senescence-associated secretory phenotype in BMAds.