E-selectin ligand 1 regulates bone remodeling by limiting bioactive TGF-β in the bone microenvironment

Yang, Tao; Grafe, Ingo; Bae, Yangjin; Chen, Shan; Chen, Yuqing; Bertin, Terry; Jiang, Mingming; Ambrose, Catherine G.; Lee, Brendan

doi:10.1073/pnas.1219748110

Cited by 33 publications

(39 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Osteometrix software was used to analyze these variables. For the measurement, one section was chosen from each lumber and femoral sample to make the location of the specimen consistent, and two observers were double-blinded to read the slides [16]. …”

Section: Methodsmentioning

confidence: 99%

Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton

Chen

Grover

Sibai

et al. 2015

Molecular Genetics and Metabolism

Self Cite

View full text Add to dashboard Cite

Angiotensin receptor blockers (ARBs) are a group of anti-hypertensive drugs that are widely used to treat pediatric hypertension. Recent application of ARBs to treat diseases such as Marfan syndrome or Alport syndrome has shown positive outcomes in animal and human studies, suggesting a broader therapeutic potential for this class of drugs. Multiple studies have reported a benefit of ARBs on adult bone homeostasis; however, its effect on the growing skeleton in children is unknown. We investigated the effect of Losartan, an ARB, in regulating bone mass and cartilage during development in mice. Wild type mice were treated with Losartan from birth until 6 weeks of age, after which bones were collected for microCT and histomorphometric analyses. Losartan increased trabecular bone volume vs. tissue volume (a 98% increase) and cortical thickness (a 9% increase) in 6-weeks old wild type mice. The bone changes were attributed to decreased osteoclastogenesis as demonstrated by reduced osteoclast number per bone surface in vivo and suppressed osteoclast differentiation in vitro. At the molecular level, Angiotensin II-induced ERK1/2 phosphorylation in RAW cells was attenuated by Losartan. Similarly, RANKL-induced ERK1/2 phosphorylation was suppressed by Losartan, suggesting a convergence of RANKL and angiotensin signaling at the level of ERK1/2 regulation. To assess the effect of Losartan on cartilage development, we examined the cartilage phenotype of wild type mice treated with Losartan in utero from conception to 1 day of age. Growth plates of these mice showed an elongated hypertrophic chondrocyte zone and increased Col10a1 expression level, with minimal changes in chondrocyte proliferation. Altogether, inhibition of the angiotensin pathway by Losartan increases bone mass and accelerates chondrocyte hypertrophy in growth plate during skeletal development.

show abstract

Section: Methodsmentioning

confidence: 99%

Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton

Chen

Grover

Sibai

et al. 2015

Molecular Genetics and Metabolism

Self Cite

View full text Add to dashboard Cite

show abstract

“…TGF-βs are synthesized as large precursor molecules, composed of mature TGF-β and latency-associated protein (LAP). LAP remains noncovalently bound to mature TGF-β as it is secreted, rendering it inactive by masking the ECM of many different tissues, if not all (52)(53)(54). TGF-β1 is one of the most abundant cytokines in the bone matrix (200 μg/kg; refs.…”

Section: Tgf-β Recruits Mscs For Bone Homeostasis During Remodelingmentioning

confidence: 99%

Bone marrow mesenchymal stem cells and TGF-β signaling in bone remodeling

Crane¹,

Cao²

2014

J. Clin. Invest.

382

300

View full text Add to dashboard Cite

During bone resorption, abundant factors previously buried in the bone matrix are released into the bone marrow microenvironment, which results in recruitment and differentiation of bone marrow mesenchymal stem cells (MSCs) for subsequent bone formation, temporally and spatially coupling bone remodeling. Parathyroid hormone (PTH) orchestrates the signaling of many pathways that direct MSC fate. The spatiotemporal release and activation of matrix TGF-β during osteoclast bone resorption recruits MSCs to bone-resorptive sites. Dysregulation of TGF-β alters MSC fate, uncoupling bone remodeling and causing skeletal disorders. Modulation of TGF-β or PTH signaling may reestablish coupled bone remodeling and be a potential therapy. IntroductionIn humans, the skeleton undergoes continuous remodeling throughout adulthood. To maintain skeletal integrity, the activity of two cell types must be precisely coordinated. Osteoclasts, which resorb bone, are multinucleated cells derived from macrophages/monocytes in the HSC lineage. Osteoblasts, which deposit calcified bone matrix, are derived from bone marrow mesenchymal stem cells (MSCs; also referred to as bone marrow stromal cells or skeletal stem cells; ref. 1). The bone remodeling cycle is characterized by three distinct phases: (a) initiation, during which osteoclasts are formed and resorb damaged bone; (b) reversal, the transition of osteoclast to osteoblast activity; and (c) formation, when osteoblasts replace the portion of bone that was resorbed (2). Key steps in the reversal period include termination of osteoclast bone resorption and recruitment/differentiation of MSCs (2). Skeletal homeostasis is maintained by precise regulatory mechanisms during the reversal phase.The bone marrow microenvironment that is created during osteoclast bone resorption directs MSC fate. During osteoclastmediated bone resorption, multiple factors are released from the bone matrix and/or secreted locally, creating an osteogenic microenvironment that promotes MSC recruitment and osteoblast differentiation for new bone formation (3-6). Parathyroid hormone (PTH), the systemic hormone that regulates calcium homeostasis, plays a major role in orchestrating bone remodeling by modulating the bone marrow microenvironment and regulating osteogenic signaling pathways (7-16). Latent TGF-β1, which is abundant in the bone matrix, is released and activated by osteoclasts to specifically induce migration of MSCs to bone-resorptive sites (17)(18)(19). Because these two pathways have specific effects on MSC fate, their coordinated regulation is critical to bone remodeling.Here, we discuss the current understanding of how the bone marrow microenvironment at resorption sites affects MSCs and contributes to coupled bone remodeling. We specifically focus on how PTH regulates the osteogenic bone marrow microenvironment and how TGF-β promotes MSC recruitment. We also describe specific skeletal diseases that result from disruption of coupled bone remodeling. Finally, we address how modulation of TGF-β or PTH signal...

show abstract

“…9 To understand how this glycoprotein may contribute to global immune and hematologic homeostasis, we set out to analyze mice deficient in ESL-1. These mice display major skeletal defects and reduced body weight 16,20 but are fertile and live for at least 40 weeks. However, the frequency of live ESL-1-deficient mice born from heterozygous parents was very low (1.7%; 7/412 live births), suggesting a high rate of embryonic lethality.…”

Section: Resultsmentioning

confidence: 99%

Coordinated and unique functions of the E-selectin ligand ESL-1 during inflammatory and hematopoietic recruitment in mice

Sreeramkumar

Leiva

Stadtmann

et al. 2013

Blood

Self Cite

View full text Add to dashboard Cite

• ESL-1 and PSGL-1 cooperate to mediate E-selectin binding, myeloid homeostasis, and inflammatory cell recruitment.• ESL-1 dominates E-selectin binding and homing of hematopoietic progenitors.Beyond its well-established roles in mediating leukocyte rolling, E-selectin is emerging as a multifunctional receptor capable of inducing integrin activation in neutrophils, and of regulating various biological processes in hematopoietic precursors. Although these effects suggest important homeostatic contributions of this selectin in the immune and hematologic systems, the ligands responsible for transducing these effects in different leukocyte lineages are not well defined. We have characterized mice deficient in E-selectin ligand-1 (ESL-1), or in both P-selectin glycoprotein-1 (PSGL-1) and ESL-1, to explore and compare the contributions of these glycoproteins in immune and hematopoietic cell trafficking. In the steady state, ESL-1 deficiency resulted in a moderate myeloid expansion that became more prominent when both glycoproteins were eliminated. During inflammation, PSGL-1 dominated E-selectin binding, rolling, integrin activation, and extravasation of mature neutrophils, but only the combined deficiency in PSGL-1 and ESL-1 completely abrogated leukocyte recruitment. Surprisingly, we find that the levels of ESL-1 were strongly elevated in hematopoietic progenitor cells. These elevations correlated with a prominent function of ESL-1 for E-selectin binding and for migration of hematopoietic progenitor cells into the bone marrow. Our results uncover dominant roles for ESL-1 in the immature compartment, and a functional shift toward PSGL-1 dependence in mature neutrophils. (Blood. 2013;122(24): 3993-4001)

show abstract

E-selectin ligand 1 regulates bone remodeling by limiting bioactive TGF-β in the bone microenvironment

Cited by 33 publications

References 37 publications

Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton

Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton

Bone marrow mesenchymal stem cells and TGF-β signaling in bone remodeling

Coordinated and unique functions of the E-selectin ligand ESL-1 during inflammatory and hematopoietic recruitment in mice

Contact Info

Product

Resources

About