The skeleton is a dynamic organ that is constantly remodeled. Proteins secreted from bone cells, namely osteoblasts, osteocytes, and osteoclasts exert regulation on osteoblastogenesis, ...osteclastogenesis, and angiogenesis in a paracrine manner. Osteoblasts secrete a range of different molecules including RANKL/OPG, M-CSF, SEMA3A, WNT5A, and WNT16 that regulate osteoclastogenesis. Osteoblasts also produce VEGFA that stimulates osteoblastogenesis and angiogenesis. Osteocytes produce sclerostin (SOST) that inhibits osteoblast differentiation and promotes osteoclast differentiation. Osteoclasts secrete factors including BMP6, CTHRC1, EFNB2, S1P, WNT10B, SEMA4D, and CT-1 that act on osteoblasts and osteocytes, and thereby influenceaA osteogenesis. Osteoclast precursors produce the angiogenic factor PDGF-BB to promote the formation of Type H vessels, which then stimulate osteoblastogenesis. Besides, the evidences over the past decades show that at least three hormones or "osteokines" from bone cells have endocrine functions. FGF23 is produced by osteoblasts and osteocytes and can regulate phosphate metabolism. Osteocalcin (OCN) secreted by osteoblasts regulates systemic glucose and energy metabolism, reproduction, and cognition. Lipocalin-2 (LCN2) is secreted by osteoblasts and can influence energy metabolism by suppressing appetite in the brain. We review the recent progresses in the paracrine and endocrine functions of the secretory proteins of osteoblasts, osteocytes, and osteoclasts, revealing connections of the skeleton with other tissues and providing added insights into the pathogenesis of degenerative diseases affecting multiple organs and the drug discovery process.
The bone marrow has been widely recognised to host a unique microenvironment that facilitates tumour colonisation. Bone metastasis frequently occurs in the late stages of malignant diseases such as ...breast, prostate and lung cancers. The biology of bone metastasis is determined by tumour-cell-intrinsic traits as well as their interaction with the microenvironment. The bone marrow is a dynamic organ in which various stages of haematopoiesis, osteogenesis, osteolysis and different kinds of immune response are precisely regulated. These different cellular components constitute specialised tissue microenvironments-niches-that play critical roles in controlling tumour cell colonisation, including initial seeding, dormancy and outgrowth. In this review, we will dissect the dynamic nature of the interactions between tumour cells and bone niches. By targeting certain steps of tumour progression and crosstalk with the bone niches, the development of potential therapeutic approaches for the clinical treatment of bone metastasis might be feasible.
Metastasis is a major contributor to cancer patient mortality. Tumour cells often develop phenotypic plasticity to successfully metastasize to different target organs. Recent progress in the study of ...bone metastasis has provided novel insight into the biological processes that drive the spread and growth of cancer cells in the bone. In this review, we provide a summary of how the bone marrow microenvironment promotes phenotypic plasticity of metastatic tumour cells and alters therapeutic responses. We highlight pivotal transformations in cellular status driven by plasticity, including mesenchymal-epithelial transition, acquisition of stem-like traits, and awakening from dormancy. Additionally, we describe the phenomenon of host-organ mimicry and metabolic rewiring that collectively serve as key attributes of disseminated tumour cells, enabling their successful colonization and growth within the bone marrow microenvironment.
Heterotopic ossification (HO) is pathological bone formation characterized by ossification within muscle, tendons, or other soft tissues. However, the cells of origin and mechanisms involved in the ...pathogenesis of HO remain elusive. Here we show that deletion of suppressor of fused (Sufu) in cathepsin K-Cre-expressing (Ctsk-Cre-expressing) cells resulted in spontaneous and progressive ligament, tendon, and periarticular ossification. Lineage tracing studies and cell functional analysis demonstrated that Ctsk-Cre could label a subpopulation of tendon-derived progenitor cells (TDPCs) marked by the tendon marker Scleraxis (Scx). Ctsk+Scx+ TDPCs are enriched for tendon stem cell markers and show the highest self-renewal capacity and differentiation potential. Sufu deficiency caused enhanced chondrogenic and osteogenic differentiation of Ctsk-Cre-expressing tendon-derived cells via upregulation of Hedgehog (Hh) signaling. Furthermore, pharmacological intervention in Hh signaling using JQ1 suppressed the development of HO. Thus, our results show that Ctsk-Cre labels a subpopulation of TDPCs contributing to HO and that their cell-fate changes are driven by activation of Hh signaling.
Mammalian target of rapamycin complex 1 (mTORC1) is involved in anabolic metabolism in both osteoblasts and chondrocytes, but the role of mTORC1 in osteoclast biology in vivo remains to be ...elucidated. In this study, we showed that deletion of regulatory-associated protein of mTOR (Raptor) in osteoclasts led to an increase in bone mass with decreased bone resorption. Raptor-deficient bone marrow-derived macrophages exhibited lower mTORC1-S6K1 signaling and retarded osteoclast differentiation, as determined by the number of osteoclasts, tartrate-resistant acid phosphatase activity, and expression of osteoclast-specific genes. Enforced expression of constitutively active S6K1 rescued the impaired osteoclast differentiation in Raptor-deficient bone marrow-derived macrophages. Furthermore, pharmacological inhibition of mTORC1 signaling by rapamycin could also inhibit osteoclast differentiation and osteoclast-specific gene expression. Taken together, our findings demonstrate that mTORC1 plays a key role in the network of catabolic bone resorption in osteoclasts and may serve as a potential pharmacological target for the regulation of osteoclast activity in bone metabolic disorders.
ABSTRACT
In order to study the effect of Hericium erinaceus polysaccharide (HEP) on the immune and antioxidation functions of immunosuppressed mice. The control group received distilled water orally ...and the model and experimental groups I, II, and III received 0, 80, 160, and 320 mg/kg HEP respectively for a fortnight after re-molding with cyoclphosphnalide (CTX). Compared with the control group, the secretion of IL-2, IL-4, and IFN-γ, the activity or content of T-AOC, T-SOD, and GSH-PX, and the expression of PCNA mRNA in the thymus and spleen were reduced in immunosuppressed mice (P < .05 or P < .01). Compared with immunosuppressed mice, the levels of IL-2, IFN-γ, and GSH-PX and the PCNA mRNA expression of spleen and thymus were increased (P < .05 or P < .01), and the microstructure were also obviously improved in the experimental group III. Overall, 320 mg/kg of HEP significantly improved the immune and antioxidant functions.
Graphical Abstract
Graphical Abstract
HEP can improve cytokine secretion by regulating antioxidant function and expression of apoptosis-related genes, thereby ameliorating tissue microstructure of thymus and spleen.
Osteoporosis caused by aging is characterized by reduced bone mass and accumulated adipocytes in the bone marrow cavity. How the balance between osteoblastogenesis and adipogenesis from bone marrow ...mesenchymal stem cells (BMSCs) is lost upon aging is still unclear. Here, we found that the RNA-binding protein Musashi2 (Msi2) regulates BMSC lineage commitment. Msi2 is commonly enriched in stem cells and tumor cells. We found that its expression was downregulated during adipogenic differentiation and upregulated during osteogenic differentiation of BMSCs. Msi2 knockout mice exhibited decreased bone mass with substantial accumulation of marrow adipocytes, similar to aging-induced osteoporosis. Depletion of Msi2 in BMSCs led to increased adipocyte commitment. Transcriptional profiling analysis revealed that Msi2 deficiency led to increased PPARγ signaling. RNA-interacting protein immunoprecipitation assays demonstrated that Msi2 could inhibit the translation of the key adipogenic factor Cebpα, thereby inhibiting PPAR signaling. Furthermore, the expression of Msi2 decreased significantly during the aging process of mice, indicating that decreased Msi2 function during aging contributes to abnormal accumulation of adipocytes in bone marrow and osteoporosis. Thus, our results provide a putative biochemical mechanism for aging-related osteoporosis, suggesting that modulating Msi2 function may benefit the treatment of bone aging.
Mutagenic screening is powerful for identifying key genes involved in developmental processes. However, such screens are successful only in lower organisms. Here, we develop a targeted genetic ...screening approach in mice through combining androgenetic haploid embryonic stem cells (AG-haESCs) and clustered regularly interspaced palindromic repeats/CRISPR-associated protein 9 (CRISPR-Cas9) technology. We produced a mutant semi-cloned (SC) mice pool by oocyte injection of AG-haESCs carrying constitutively expressed Cas9 and an single guide RNA (sgRNA) library targeting 72 preselected genes in one step and screened for bone-development-related genes through skeletal analysis at birth. This yielded 4 genes: Zic1 and Clec11a, which are required for bone development, and Rln1 and Irx5, which had not been previously considered. Whereas Rln1-/- mice exhibited small skeletal size only at birth, Irx5-/- mice showed skeletal abnormalities both in postnatal and adult phases due to decreased bone mass and increased bone marrow adipogenesis. Mechanistically, iroquois homeobox 5 (IRX5) promotes osteoblastogenesis and inhibits adipogenesis by suppressing peroxisome proliferator activated receptor γ (PPARγ) activation. Thus, AG-haESC-mediated functional mutagenic screening opens new avenues for genetic interrogation of developmental processes in mice.
Low-salinity water (LSW) flooding technology has obvious operational and economic advantages, so it is applied to practice in many oilfields. However, there are differences in the oil recovery ...efficiencies in different oilfields, the reasons for which need to be further studied and discussed. This paper studies the effect of different clay mineral compositions on low-salinity water flooding. For this purpose, three groups of core displacement experiments were designed with cores containing different clay mineral compositions for comparison. In the process of formation water and low-salinity water driving, the oil recovery and produced-water properties were measured. By comparing the two types of water flooding, it was found that the cores with the highest montmorillonite content had the best effect (5.7%) on low-salinity water flooding and the cores with the highest kaolinite content had the least effect (1.9%). This phenomenon is closely related to the difference in ion exchange capacity of the clay minerals. Moreover, after switching to low-salinity water flooding, the interfacial tension and wetting angle of the produced-water increased and the value of pH decreased, which are important mechanisms for enhancing oil recovery by low-salinity water flooding. This study reveals the influence of clay mineral composition on low-salinity water flooding and can provide more guidance for conventional and unconventional oilfield application of low-salinity water flooding technology.
The proper supplementation of boron, an essential trace element, can enhance animal immune function. We utilized the method of TMT peptide labeling in conjunction with LC-MS/MS quantitative ...proteomics for the purpose of examining the effects of boric acid on a rat model and analyzing proteins from the duodenum. In total, 5594 proteins were obtained from the 0, 10, and 320 mg/L boron treatment groups. Two hundred eighty-four proteins that exhibit differential expression were detected. Among the comparison, groups of 0 vs. 10 mg/L, 0 vs. 320 mg/L, and 10 vs. 320 mg/L of boron, 110, 32, and 179 proteins, respectively, demonstrated differential expression. The results revealed that these differential expression proteins (DEPs) mainly clustered into two profiles. GO annotations suggested that most of the DEPs played a role in the immune system process, in which 2′-5′-oligoadenylate synthetase-like, myxovirus resistance 1, myxovirus resistance 2, dynein cytoplasmic 1 intermediate chain 1, and coiled-coil domain containing 88B showed differential expression. The DEPs had demonstrated an augmentation in the signaling pathways, which primarily include phagosome, antigen processing, and presentation, as well as cell adhesion molecules (CAMs). Our study found that immune responses in the duodenum were enhanced by lower doses of boron and that this effect is likely mediated by changes in protein expression patterns in related signaling pathways. It offers an in-depth understanding of the underlying molecular mechanisms that lead to immune modulation in rats subjected to dietary boron treatment.
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