Bone marrow mesenchymal lineage cells are a heterogeneous cell population involved in bone homeostasis and diseases such as osteoporosis. While it is long postulated that they originate from mesenchymal stem cells, the true identity of progenitors and their in vivo bifurcated differentiation routes into osteoblasts and adipocytes remain poorly understood. Here, by employing large scale single cell transcriptome analysis, we computationally defined mesenchymal progenitors at different stages and delineated their bi-lineage differentiation paths in young, adult and aging mice. One identified subpopulation is a unique cell type that expresses adipocyte markers but contains no lipid droplets. As non-proliferative precursors for adipocytes, they exist abundantly as pericytes and stromal cells that form a ubiquitous 3D network inside the marrow cavity. Functionally they play critical roles in maintaining marrow vasculature and suppressing bone formation. Therefore, we name them marrow adipogenic lineage precursors (MALPs) and conclude that they are a newly identified component of marrow adipose tissue.
The clinical findings that alendronate blunted the anabolic effect of human parathyroid hormone (PTH) on bone formation suggest that active resorption is involved and enhances the anabolic effect. PTH signals via its receptor on the osteoblast membrane, and osteoclasts are impacted indirectly via the products of osteoblasts. Microarray with RNA from rats injected with human PTH or vehicle showed a strong association between the stimulation of monocyte chemoattractant protein-1 (MCP-1) and the anabolic effects of PTH. PTH rapidly and dramatically stimulated MCP-1 mRNA in the femora of rats receiving daily injections of PTH or in primary osteoblastic and UMR 106-01 cells. The stimulation of MCP-1 mRNA was dose-dependent and a primary response to PTH signaling via the cAMP-dependent protein kinase pathway in vitro. Studies with the mouse monocyte cell line RAW 264.7 and mouse bone marrow proved that osteoblastic MCP-1 can potently recruit osteoclast monocyte precursors and facilitate receptor activator of NF-B ligand-induced osteoclastogenesis and, in particular, enhanced fusion. Our model suggests that PTH-induced osteoblastic expression of MCP-1 is involved in recruitment and differentiation at the stage of multinucleation of osteoclast precursors. This information provides a rationale for increased osteoclast activity in the anabolic effects of PTH in addition to receptor activator of NF-B ligand stimulation to initiate greater bone remodeling. Parathyroid hormone (PTH)2 is a principal hormone regulating bone remodeling via its actions on both bone formation and bone resorption. The finding that the anabolic effect of human PTH-(1-34) on bone formation was blunted when bone resorption was inhibited indicated that active resorption is involved and enhances the in vivo anabolic effect of PTH (1-3). However, the molecular basis of the osteoclast activation in this process has not been fully studied. In order to identify the key mediators for the anabolic effects of PTH, we performed microarray using RNA from the femora of 3-month-old Sprague-Dawley female rats injected daily with hPTH-(1-34) to increase bone formation or vehicle. This was compared with rats receiving hPTH-(1-34) in a catabolic protocol by continuous infusion. PTH-(1-34) regulated numerous genes (ϳ1,000), but differentially, in both regimes (see accompanying article, Ref. 4). Notably, in the anabolic protocol, a number of cytokines and chemokines, RANKL, interleukin-6, CXCL1, and CCL2 (MCP-1), were highly induced. In contrast, none of these were significantly increased, by microarray, in the catabolic protocol. The chemokine, monocyte chemoattractant protein-1 (MCP-1, CCL2), was found to be the most highly stimulated gene from 14-day intermittent hPTH-(1-34) or hPTH-(1-31) administration (both cause over 100-fold changes). With continuous infusion of PTH, the MCP-1 mRNA was elevated less than 2-fold, and this difference indicates a potentially important role for MCP-1 in the anabolic effect of PTH.Chemokines are bioactive peptides that regulate leuk...
Osteosarcoma is the most common type of solid bone cancer and the second leading cause of cancer-related death in pediatric patients. Many patients are not cured by the current osteosarcoma therapy consisting of combination chemotherapy along with surgery and thus new treatments are urgently needed. In the last decade, cancer stem cells have been identified in many tumors such as leukemia, brain, breast, head and neck, colon, skin, pancreatic, and prostate cancers and these cells are proposed to play major roles in drug resistance, tumor recurrence, and metastasis. Recent studies have shown evidence that osteosarcoma also possesses cancer stem cells. This review summarizes the current knowledge about the osteosarcoma cancer stem cell including the methods used for its isolation, its properties, and its potential as a new target for osteosarcoma treatment.
Parathyroid hormone (PTH) stimulates bone formation when injected daily but causes severe bone loss with continuous infusion. The mechanism of its paradoxical effects is still elusive. In this study, we compared changes in the gene expression profile in bone induced by intermittent or continuous treatment with three different PTH peptides, PTH-(1-34), -(1-31), and -(3-34), in Sprague-Dawley female rats. PTH-(1-34) regulated numerous genes (ϳ1,000), but differentially, in both regimes. PTH-(1-31) regulated a similar number of genes in the intermittent regimen but fewer in the continuous regimen, consistent with its less potent catabolic effect. PTH-(3-34) regulated very few genes in both regimes, which suggests the protein kinase C pathway plays a limited role in mediating the dual effects of PTH, whereas the cAMPdependent protein kinase A pathway appears to predominate. In the intermittent treatment, many genes encoding signaling mediators, transcription factors, cytokines, and proteases/ protease inhibitors are regulated rapidly and cyclically with each PTH injection; genes associated with skeletal development show a slowly accruing pattern of expression. With continuous treatment, some genes are regulated from 6 h, and the mRNA levels are sustained with a longer infusion, whereas others show a kinetic decrease and then increase later. Significant up-regulation of genes stimulating osteoclastogenesis in the anabolic regime suggests a provocative and paradoxical theme for the anabolic effect of PTH that a full anabolic response requires a transient up-regulation of genes classically associated with a resorptive response. Ingenuity pathway analysis was performed on the microarray data. A novel signaling network was established that is differentially regulated in the two PTH treatment regimes. Key regulators are suggested to be AREG, CCL2, WNT4, and cAMP-responsive element modulator. PTH,2 administered intermittently, stimulates bone formation in contrast to antiresorptive agents, which reduce bone resorption. Concerns with the limited improvement of antiresorptive treatments in severe osteoporosis led to a search for alternative anabolic agents (1). Teraparatide, recombinant human parathyroid hormone consisting of the first 34 of the 84 amino acids of human parathyroid hormone, has been shown to reduce significantly the risk of both vertebral and nonvertebral fractures in postmenopausal women and to significantly increase bone mineral density (2). It has become the only anabolic agent currently approved for the treatment of osteoporosis in the United States.Bone is a highly specialized form of connective tissue and dynamic organ in all higher vertebrates; it undergoes continuous regeneration. Bone remodeling occurs at discrete sites within the skeleton and proceeds in an orderly fashion, with coupling of osteoclastic resorption and osteoblastic formation (3). This physiological process is coordinated and tightly regulated by local and endocrine factors to ensure that there is a balance between bone formation and ...
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