Reporting guidelines, review of methodological standards, and challenges toward harmonization in bone marrow adiposity research. Report of the Methodologies Working Group of the International Bone Marrow Adiposity Society

The interest in bone marrow adiposity (BMA) has increased over the last decade due to its association with, and potential role, in a range of diseases (osteoporosis, diabetes, anorexia, cancer) as well as treatments (corticosteroid, radiation, chemotherapy, thiazolidinediones). However, to advance the field of BMA research, standardization of methods is desirable to increase comparability of study outcomes and foster collaboration. Therefore, at the 2017 annual BMA meeting, the International Bone Marrow Adiposity Society (BMAS) founded a working group to evaluate methodologies in BMA research. All BMAS members could volunteer to participate. The working group members, who are all active preclinical or clinical BMA researchers, searched the literature for articles investigating BMA and discussed the results during personal and telephone conferences. According to the consensus opinion, both based on the review of the literature and on expert opinion, we describe existing methodologies and discuss the challenges and future directions for (1) histomorphometry of bone marrow adipocytes, (2

MarrowQuant across aging and aplasia: A digital pathology workflow for quantification of bone marrow compartments in histological sections

The bone marrow (BM) exists heterogeneously as hematopoietic/red or adipocytic/yellow marrow depending on skeletal location, age, and physiological condition. Mouse models and patients undergoing radio/chemotherapy or suffering acute BM failure endure rapid adipocytic conversion of the marrow microenvironment, the so-called red-to-yellow transition. Following hematopoietic recovery, such as upon BM transplantation, a yellow-to-red transition occurs and functional hematopoiesis is restored. Gold Standards to estimate BM cellular composition are pathologists\u27 assessment of hematopoietic cellularity in hematoxylin and eosin (H&E) stained histological sections as well as volumetric measurements of marrow adiposity with contrast-enhanced micro-computerized tomography (CE-μCT) upon osmium-tetroxide lipid staining. Due to user-dependent variables, reproducibility in longitudinal studies is a challenge for both methods. Here we report the development of a semi-automated image analysis plug-in

Regulation of Bone Formation and Pathology by Local Actions of Leptin in the Bone Marrow.

Site-specific adipose content of the bone marrow has been noted since the inclusion of meat into the hominid diet, evidenced by marrow removal from ungulate limb bones, 2.6 million years ago. Association between marrow fat and bone metabolism has since been documented, however the mechanism for this relationship remains unknown. Leptin, a secreted adipocytokine, possesses the ability to regulate bone formation centrally through the hypothalamus and peripherally though marrow cells such as the osteoblast. Until the recent generation of a mouse with loxP sites flanking exon17 of the signaling-competent leptin receptor (ObRb), the physiologic contribution of peripheral leptin signaling to bone formation could not be determined. Leptin has been shown to increase mineralization of primary bone marrow stromal precursor cells (MPCs) and osteoblasts in vitro. Leptin is also a potent regulator of pro-inflammatory macrophage cytokine output. We therefore examined the ability of leptin to modulate bone formation through the myeloid lineage, the osteoblast, and the MPC by generating mice with conditional deletion of ObRb using LysozymeM 2 (LysM), Col2.3, and Col3.6 promoters driving Cre recombinase respectively. Myeloid-specific deletion of ObRb resulted in a mild, gender-specific bone phenotype in 52 week old animals with decreases in trabecular parameters noted in females and increases in cortical values in males. This change mimics associations between circulating leptin and bone mineral density (BMD) observed in adult humans. Osteoblast ObRb deletion using Col2.3-Cre did not produce a discernable bone phenotype. However, conditional removal of ObRb with Col3.6-Cre on more primitive MPCs increased femoral length and trabecular and cortical femoral parameters at 12 and 52 weeks of age. Our results imply that at physiologic equilibrium, leptin regulation of mature osteoblast function is negligible, however, early modulation of MPCs may contribute to properties such as bone length and trabecular formation. In contrast, regulation of myeloid lineage cells such as macrophages may explain adult gender-specific differences in associations between circulating leptin and BMD. Further modulation of macrophage-associated leptin signaling by compounds such as amino-bisphosphonates may enhance the ability of leptin to contribute to bone formation as well as the pathogenesis of diseases such as osteonecrosis of the jaw.Ph.D.Oral Health SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/89775/1/scheller_1.pd

A maternal brain hormone that builds bone

In lactating mothers, the high calcium (C

Report from the 6th International Meeting on Bone Marrow Adiposity (BMA2020)

The

The Performance Appraisal Interview – An Arena for the Reinforcement of Norms for Employeeship

In the present paper, we report findings from a study of performance appraisal interviews between middle managers and employees. The study is based on analysis of video uptake of authentic performance appraisal interviews, and through detailed examination of participant conduct and orientation, we point to structural mechanisms and institutional norms which limit the possibilities for employees to raise topics connected to negative experiences of stress in performance ap- praisal talk. It is argued that norms concerning ideal employeeship are shaped by a partly hidden curriculum in the organization which in turn is talked into being in the performance appraisal interviews.The study concludes that empirical attention to the social interplay in performance ap- praisal interactions reveal how participant conduct aligns or disaligns with institutional and social underpinnings of workplace ideals

A neuroskeletal atlas: Spatial mapping and contextualization of axon subtypes innervating the long bones of C3H and B6 mice

Nerves in bone play well-established roles in pain and vasoregulation and have been associated with progression of skeletal disorders, including osteoporosis, fracture, arthritis, and tumor metastasis. However, isolation of the region-specific mechanisms underlying these relationships is limited by our lack of quantitative methods for neuroskeletal analysis and precise maps of skeletal innervation. To overcome these limitations, we developed an optimized workflow for imaging and quantitative analysis of axons in and around the bone, including validation of Baf53b-Cre in concert with R26R-tdTomato (Ai9) as a robust pan-neuronal reporter system for use in musculoskeletal tissues. In addition, we created comprehensive maps of sympathetic adrenergic and sensory peptidergic axons within and around the full length of the femur and tibia in two strains of mice (B6 and C3H). In the periosteum, these maps were related to the surrounding musculature, including entheses and myotendinous attachments to bone. Three distinct patterns of periosteal innervation (termed type I, II, III) were defined at sites that are important for bone pain, bone repair, and skeletal homeostasis. For the first time, our results establish a gradient of bone marrow axon density that increases from proximal to distal along the length of the tibia and define key regions of interest for neuroskeletal studies. Lastly, this information was related to major nerve branches and local maps of specialized mechanoreceptors. This detailed mapping and contextualization of the axonal subtypes innervating the skeleton is intended to serve as a guide during the design, implementation, and interpretation of future neuroskeletal studies and was compiled as a resource for the field as part of the NIH SPARC consortium. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Role of the peripheral nervous system in skeletal development and regeneration: Controversies and clinical implications

PURPOSE OF REVIEW: This review examines the diverse functional relationships that exist between the peripheral nervous system (PNS) and bone, including key advances over the past century that inform our efforts to translate these discoveries for skeletal repair. RECENT FINDINGS: The innervation of the bone during development, homeostasis, and regeneration is highly patterned. Consistent with this, there have been nearly 100 studies over the past century that have used denervation approaches to isolate the effects of the different branches of the PNS on the bone. Overall, a common theme of balance emerges whereby an orchestration of both local and systemic neural functions must align to promote optimal skeletal repair while limiting negative consequences such as pain. An improved understanding of the functional bidirectional pathways linking the PNS and bone has important implications for skeletal development and regeneration. Clinical advances over the next century will necessitate a rigorous identification of the mechanisms underlying these effects that is cautious not to oversimplify the in vivo condition in diverse states of health and disease