Publications by authors named "Sylvain Provot"

WHIM Syndrome is a rare immunodeficiency caused by gain-of-function CXCR4 mutations. Here we report a decrease in bone mineral density in 25% of WHIM patients and bone defects leading to osteoporosis in a WHIM mouse model. Imbalanced bone tissue is observed in mutant mice combining reduced osteoprogenitor cells and increased osteoclast numbers.

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Article Synopsis
  • Breast cancer is the most prevalent cancer globally and a leading cause of cancer deaths among women, with studies linking night-shift work and circadian disruption to increased cancer risk.
  • The research uses a mouse model to explore how chronic jetlag affects mammary tumor development, revealing that circadian disruption accelerates cancer spread and alters the tumor environment.
  • The findings suggest that using a CXCR2 inhibitor may help counteract the negative effects of chronic circadian disruption on breast cancer progression.
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The bioactive lipid mediator sphingosine 1-phosphate (S1P) was recently assigned critical roles in platelet biology: whereas S1P receptor-mediated S1P gradient sensing was reported to be essential for directing proplatelet extensions from megakaryocytes (MKs) toward bone marrow sinusoids, MK sphingosine kinase 2 (Sphk2)-derived S1P was reported to further promote platelet shedding through receptor-independent intracellular actions, and platelet aggregation through S1P Yet clinical use of S1P pathway modulators including fingolimod has not been associated with risk of bleeding or thrombosis. We therefore revisited the role of S1P in platelet biology in mice. Surprisingly, no reduction in platelet counts was observed when the vascular S1P gradient was ablated by impairing S1P provision to plasma or S1P degradation in interstitial fluids, nor when gradient sensing was impaired by deletion selectively in MKs.

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During skeletal mineralization, the sodium-phosphate co-transporter PiT1Slc20a1 is assumed to meet the phosphate requirements of bone-forming cells, although evidence is missing. Here, we used a conditional gene deletion approach to determine the role of PiT1 in growth plate chondrocytes. We show that PiT1 ablation shortly after birth generates a rapid and massive cell death in the center of the growth plate, together with an uncompensated endoplasmic reticulum (ER) stress, characterized by morphological changes and increased Chop, Atf4, and Bip expression.

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Sarcomas are still unsolved therapeutic challenges. Cancer stem cells are believed to contribute to sarcoma development, but lack of specific markers prevents their characterization and targeting. Here, we show that calpain-6 expression is associated with cancer stem cell features.

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Bone metastasis involves dynamic interplay between tumor cells and the local stromal environment. In bones, local hypoxia and activation of the hypoxia-inducible factor (HIF)-1α in osteoblasts are essential to maintain skeletal homeostasis. However, the role of osteoblast-specific HIF signaling in cancer metastasis is unknown.

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Low oxygen tension (hypoxia) regulates chondrocyte differentiation and metabolism. Hypoxia-inducible factor 1α (HIF1α) is a crucial hypoxic factor for chondrocyte growth and survival during development. The major metalloproteinase matrix metalloproteinase 13 (MMP13) is also associated with chondrocyte hypertrophy in adult articular cartilage, the lack of which protects from cartilage degradation and osteoarthritis (OA) in mice.

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In spite of a good understanding of the cellular and molecular mechanisms responsible for neoplastic transformation, most cancer therapies remain partially effective and transient. Recent studies established the importance of the tumor microenvironment in tumor growth and dissemination, and in the resistance to antitumor therapies. This review summarizes our current knowledge of the local and systemic effects, sometimes surprising, which result from interactions between neoplastic cancer cells and their microenvironment.

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Despite advances in our understanding of breast cancer, patients with metastatic disease have poor prognoses. GATA3 is a transcription factor that specifies and maintains mammary luminal epithelial cell fate, and its expression is lost in breast cancer, correlating with a worse prognosis in human patients. Here, we show that GATA3 promotes differentiation, suppresses metastasis and alters the tumour microenvironment in breast cancer by inducing microRNA-29b (miR-29b) expression.

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Wdr5, a bone morphogenetic protein 2 (BMP-2)-induced protein belonging to the family of the WD repeat proteins, is expressed in proliferating and hypertrophic chondrocytes of the growth plate and in osteoblasts. Although previous studies have provided insight into the mechanisms by which Wdr5 affects chondrocyte and osteoblast differentiation, whether Wdr5 is required in vivo for endochondral bone development has not been addressed. In this study, using an avian replication competent retrovirus (RCAS) system delivering Wdr5 short hairpin (sh) RNA to silence Wdr5 in the developing limb, we report that reduction of Wdr5 levels delays endochondral bone development and consequently results in shortening of the skeletal elements.

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There is increasing evidence that the numerous mechanisms that regulate cell differentiation during normal development are also involved in tumorigenesis. In breast cancer, differentiation markers expressed by the primary tumor are routinely profiled to guide clinical decisions. Indeed, numerous studies have shown that the differentiation profile correlates with the metastatic potential of tumors.

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Fetal growth plate chondrocyte is a unique mesenchymal tissue, as it is avascular and hypoxic. Yet, chondrocytes not only survive in this environment, but also undergo all cellular processes (proliferation, growth arrest, differentiation, etc.) required for normal endochondral bone development.

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Parathyroid hormone-related peptide (PTHrP) and the parathyroid hormone-PTHrP receptor increase chondrocyte proliferation and delay chondrocyte maturation in endochondral bone development at least partly through cyclic AMP (cAMP)-dependent signaling pathways. Because data suggest that the ability of cAMP to stimulate cell proliferation involves the mitogen-activated protein kinase kinase kinase B-Raf, we hypothesized that B-Raf might mediate the proliferative action of PTHrP in chondrocytes. Though B-Raf is expressed in proliferative chondrocytes, its conditional removal from cartilage did not affect chondrocyte proliferation and maturation or PTHrP-induced chondrocyte proliferation and PTHrP-delayed maturation.

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Recent evidence suggests that low oxygen tension (hypoxia) may control fetal development and differentiation. A crucial mediator of the adaptive response of cells to hypoxia is the transcription factor Hif-1alpha. In this study, we provide evidence that mesenchymal condensations that give origin to endochondral bones are hypoxic during fetal development, and we demonstrate that Hif-1alpha is expressed and transcriptionally active in limb bud mesenchyme and in mesenchymal condensations.

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Parathyroid hormone-related protein (PTHrP) is essential to maintain a pool of dividing, immature chondrocytes in the growth plate of long bones. In chick and mouse, expression of Nkx3.2/Bapx1 in the growth plate is restricted to the proliferative zone and is down regulated as chondrocyte maturation begins.

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Endochondral bone development is a complex process in which undifferentiated mesenchymal cells differentiate into chondrocytes, which then undergo well-ordered and controlled phases of proliferation, hypertrophic differentiation, death, blood vessel invasion, and finally replacement of cartilage with bone. The process recapitulates basic and fundamental mechanisms of cell biology with a highly specific spatial and temporal pattern, and it thus constitutes an excellent model for the analysis of such mechanisms. In recent years, the tools provided by modern genetic both in mice and men have been instrumental in the process of identifying and dissecting basic molecular mechanisms of endochondral bone formation.

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Endochondral bone development is a fascinating story of proliferation, maturation, and death. An understanding of this process at the molecular level is emerging. In particular, significant advances have been made in understanding the role of parathyroid-hormone-related peptide (PTHrP), parathyroid hormone (PTH), and the PTH/PTHrP receptor in endochondral bone development.

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