Bone marrow adipogenic lineage precursors promote osteoclastogenesis in bone remodeling and pathologic bone loss

Yu, Wei; Zhong, Leilei; Yao, Lutian; Wei, Yulong; Gui, Tao; Li, Ziqing; Kim, Hyunsoo; Holdreith, Nicholas; Jiang, Xi; Tong, Wei; Dyment, Nathaniel A.; Liu, X. Sherry; Yang, Shuting; Choi, Yongwon; Ahn, Jaimo; Qin, Ling

doi:10.1172/jci140214

Cited by 118 publications

(117 citation statements)

References 66 publications

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“…To ensure the high quality of the osteoblasts data for downstream analysis, we further removed osteoblasts with more than 5% of the transcripts attributed to mitochondrial genes, following the quality control criterion applied in several scRNA-seq studies in bone field [ 37 – 39 ]. 5,329 high quality sequenced osteoblasts were retained for downstream analysis.…”

Section: Resultsmentioning

confidence: 99%

A systematic dissection of human primary osteoblasts in vivo at single-cell resolution

Gong

Yang

et al. 2021

Aging

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Human osteoblasts are multifunctional bone cells, which play essential roles in bone formation, angiogenesis regulation, as well as maintenance of hematopoiesis. However, the categorization of primary osteoblast subtypes in vivo in humans has not yet been achieved. Here, we used single-cell RNA sequencing (scRNA-seq) to perform a systematic cellular taxonomy dissection of freshly isolated human osteoblasts from one 31-year-old male with osteoarthritis and osteopenia after hip replacement. Based on the gene expression patterns and cell lineage reconstruction, we identified three distinct cell clusters including preosteoblasts, mature osteoblasts, and an undetermined rare osteoblast subpopulation. This novel subtype was found to be the major source of the nuclear receptor subfamily 4 group A member 1 and 2 (NR4A1 and NR4A2) in primary osteoblasts, and the expression of NR4A1 was confirmed by immunofluorescence staining on mouse osteoblasts in vivo . Trajectory inference analysis suggested that the undetermined cluster, together with the preosteoblasts, are involved in the regulation of osteoblastogenesis and also give rise to mature osteoblasts. Investigation of the biological processes and signaling pathways enriched in each subpopulation revealed that in addition to bone formation, preosteoblasts and undetermined osteoblasts may also regulate both angiogenesis and hemopoiesis. Finally, we demonstrated that there are systematic differences between the transcriptional profiles of human and mouse osteoblasts, highlighting the necessity for studying bone physiological processes in humans rather than solely relying on mouse models. Our findings provide novel insights into the cellular heterogeneity and potential biological functions of human primary osteoblasts at the single-cell level.

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Section: Resultsmentioning

confidence: 99%

A systematic dissection of human primary osteoblasts in vivo at single-cell resolution

Gong

Yang

et al. 2021

Aging

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“…Yu et al identified novel marrow adipogenic lineage precursors (MALPs), making up a ubiquitously distributed 3D network in bone marrow to maintain bone marrow capillary structure and suppress osteogenesis. The recent published paper further revealed that MALPs expressed RANKL and showed spatial specificity in controlling the osteoclastogenesis during bone remodeling, confirming the role of MALPs in bone resorption in physiologic and pathologic states (Yu et al, 2021). Additionally, a unique subset of macrophages named as arthritis-associated osteoclastogenic macrophages (AtoMs) was identified, which functioned as the precursor of osteoclasts in arthritis (Hasegawa et al, 2019).…”

Section: Co-development Of the Skeletal And Immune Systems Shared Molecular Mechanism Between Osteoimmune Cells In Osteoclastogenesismentioning

confidence: 71%

Current Understanding of Osteoimmunology in Certain Osteoimmune Diseases

Zhou

et al. 2021

Front. Cell Dev. Biol.

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The skeletal system and immune system seem to be two independent systems. However, there in fact are extensive and multiple crosstalk between them. The concept of osteoimmunology was created to describe those interdisciplinary events, but it has been constantly updated over time. In this review, we summarize the interactions between the skeletal and immune systems in the co-development of the two systems and the progress of certain typical bone abnormalities and bone regeneration on the cellular and molecular levels according to the mainstream novel study. At the end of the review, we also highlighted the possibility of extending the research scope of osteoimmunology to other systemic diseases. In conclusion, we propose that osteoimmunology is a promising perspective to uncover the mechanism of related diseases; meanwhile, a study from the point of view of osteoimmunology may also provide innovative ideas and resolutions to achieve the balance of internal homeostasis.

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“…For instance, Beekman et al [ 76 ] showed that OVX significantly increases the percentage of RANKL bone marrow expressing adipocytes compared to SHAM operated controls. More recently it was shown that increased bone resorption in OVX mice was partially attenuated by suppressing RANKL expression on bone marrow adipogenic precursors [ 77 ]. PPAR-γ mediated activation of c-fos has also been shown to mediate osteoclast differentiation independently of RANKL [ 78 ] which could also mechanistically explain the association between marrow adiposity and increased bone resorption in our results.…”

Section: Discussionmentioning

confidence: 99%

Association between Visceral and Bone Marrow Adipose Tissue and Bone Quality in Sedentary and Physically Active Ovariectomized Wistar Rats

Fonseca

Bezerra

Coelho

et al. 2021

Life

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Background: Obesity is considered protective for bone mass, but this view has been progressively challenged. Menopause is characterized by low bone mass and increased adiposity. Our aim was to determine how visceral and bone marrow adiposity change following ovariectomy (OVX), how they correlate with bone quality and if they are influenced by physical activity. Methods: Five-month-old Wistar rats were OVX or sham-operated and maintained in sedentary or physically active conditions for 9 months. Visceral and bone marrow adiposity as well as bone turnover, femur bone quality and biomechanical properties were assessed. Results: OVX resulted in higher weight, visceral and bone marrow adiposity. Visceral adiposity correlated inversely with femur Ct.Th (r = −0.63, p < 0.001), BV/TV (r = −0.67, p < 0.001), Tb.N (r = −0.69, p < 0.001) and positively with Tb.Sp (r = 0.58, p < 0.001). Bone marrow adiposity also correlated with bone resorption (r = 0.47, p < 0.01), bone formation rate (r = −0.63, p < 0.01), BV/TV (r = −0.85, p < 0.001), Ct.Th (r = −0.51, p < 0.0.01), and with higher empty osteocyte lacunae (r = 0.39, p < 0.05), higher percentage of osteocytes with oxidative stress (r = 0.64, p < 0.0.01) and lower femur maximal stress (r = −0.58, p < 0.001). Physical activity correlated inversely with both visceral (r = −0.74, p < 0.01) and bone marrow adiposity (r = −0.92, p < 0.001). Conclusions: OVX increases visceral and bone marrow adiposity which are associated with inferior bone quality and biomechanical properties. Physical activity could contribute to reduce adipose tissue and thereby improve bone quality.

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Bone marrow adipogenic lineage precursors promote osteoclastogenesis in bone remodeling and pathologic bone loss

Cited by 118 publications

References 66 publications

A systematic dissection of human primary osteoblasts in vivo at single-cell resolution

A systematic dissection of human primary osteoblasts in vivo at single-cell resolution

Current Understanding of Osteoimmunology in Certain Osteoimmune Diseases

Association between Visceral and Bone Marrow Adipose Tissue and Bone Quality in Sedentary and Physically Active Ovariectomized Wistar Rats

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