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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.

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.

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.

Purpose of the ReviewThe purpose of this review is to describe the in vitro and in vivo methods that researchers use to model and investigate bone marrow adipocytes (BMAds).Recent FindingsThe bone marrow (BM) niche is one of the most interesting and dynamic tissues of the human body. Relatively little is understood about BMAds, perhaps in part because these cells do not easily survive flow cytometry and histology processing and hence have been overlooked. Recently, researchers have developed in vitro and in vivo models to study normal function and dysfunction in the BM niche. Using these models, scientists and clinicians have noticed that BMAds, which form bone marrow adipose tissue (BMAT), are able to respond to numerous signals and stimuli, and communicate with local cells and distant tissues in the body.SummaryThis review provides an overview of how BMAds are modeled and studied in vitro and in vivo.

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.

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.

Cancers that grow in the bone marrow are for most patients scary, painful, and incurable. These cancers are especially hard to treat due to the supportive microenvironment provided by the bone marrow niche in which they reside. New therapies designed to target tumor cells have extended the life expectancy for these patients, but better therapies are needed and new ideas for how to target these cancers are crucial. This need has led researchers to interrogate whether bone marrow adipocytes (BMAds), which increase in number and size during aging and in obesity, contribute to cancer initiation or progression within the bone marrow. Across the globe, the consensus in the field is a unified “yes”. However, how to target these adipocytes or the factors they produce and how BMAds interact with different tumor cells are open research questions. Herein, we review this research field, with the goal of accelerating research in the network of laboratories working in this area and attracting bright scientists with new perspectives and ideas to the field in order to bring about better therapies for patients with bone cancers.

Multiple myeloma is an incurable plasma cell malignancy with only a 53% 5-year survival rate. There is a critical need to find new multiple myeloma vulnerabilities and therapeutic avenues. Herein, we identified and explored a novel multiple myeloma target: the fatty acid binding protein (FABP) family. In our work, myeloma cells were treated with FABP inhibitors (BMS3094013 and SBFI-26) and examined in vivo and in vitro for cell cycle state, proliferation, apoptosis, mitochondrial membrane potential, cellular metabolism (oxygen consumption rates and fatty acid oxidation), and DNA methylation properties. Myeloma cell responses to BMS309403, SBFI-26, or both, were also assessed with RNA sequencing (RNA-Seq) and proteomic analysis, and confirmed with western blotting and qRT-PCR. Myeloma cell dependency on FABPs was assessed using the Cancer Dependency Map (DepMap). Finally, MM patient datasets (CoMMpass and GEO) were mined for FABP expression correlations with clinical outcomes. We found that myeloma cells treated with FABPi or with FABP5 knockout (generated via CRISPR/Cas9 editing) exhibited diminished proliferation, increased apoptosis, and metabolic changes in vitro. FABPi had mixed results in vivo, in two pre-clinical MM mouse models, suggesting optimization of in vivo delivery, dosing, or type of FABP inhibitors will be needed before clinical applicability. FABPi negatively impacted mitochondrial respiration and reduced expression of MYC and other key signaling pathways in MM cells in vitro. Clinical data demonstrated worse overall and progression-free survival in patients with high FABP5 expression in tumor cells. Overall, this study establishes the FABP family as a potentially new target in multiple myeloma. In MM cells, FABPs have a multitude of actions and cellular roles that result in the support of myeloma progression. Further research into the FABP family in MM is warrented, especially into the effective translation of targeting these in vivo.

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.