FOXC1 and FOXC2 regulate growth plate chondrocyte maturation towards hypertrophy in the embryonic mouse limb skeleton.

The Forkhead box transcription factors FOXC1 and FOXC2 are expressed in condensing mesenchyme cells at the onset of endochondral ossification. We used the Prx1-cre mouse to ablate Foxc1 and Foxc2 in limb skeletal progenitor cells. Prx1-cre;Foxc1Δ/Δ;Foxc2Δ/Δ limbs were shorter than controls, with worsening phenotypes in distal structures.

Investigating drivers of telecare acceptance to improve healthcare quality for independently living older adults.

Contemporary telecare systems facilitate the ability for older adults to age in place, keeping them out of residential care facilities and providing numerous quality-of-life advantages for both care receivers (CRs) and caregivers (CGs). However, despite the acceptance of digital health interventions among older adults and their CGs, telecare adoption has been slower than expected. This paper aimed to compare attitudes toward adopting telecare systems between CRs (aging adults) and their CGs (family/friends).

Reproductive care in community health centers: Multi-method evaluation of the Illinois Contraceptive Access Now (ICAN!) demonstration program.

Objectives: Nearly one-third of low-income women of reproductive age in the U.S. receive care in federally qualified community health centers, but comprehensive reproductive care is not consistently provided.

and function in osteochondral progenitors for the progression through chondrocyte hypertrophy and mineralization of the primary ossification center.

The forkhead box transcription factor genes and are expressed in the condensing mesenchyme of the developing skeleton prior to the onset of chondrocyte differentiation. To determine the roles of these transcription factors in limb development we deleted both and in lateral plate mesoderm using the Prx1-cre mouse line. Resulting compound homozygous mice died shortly after birth with exencephaly, and malformations to this sternum and limb skeleton.

Creb5 coordinates synovial joint formation with the genesis of articular cartilage.

While prior work has established that articular cartilage arises from Prg4-expressing perichondrial cells, it is not clear how this process is specifically restricted to the perichondrium of synovial joints. We document that the transcription factor Creb5 is necessary to initiate the expression of signaling molecules that both direct the formation of synovial joints and guide perichondrial tissue to form articular cartilage instead of bone. Creb5 promotes the generation of articular chondrocytes from perichondrial precursors in part by inducing expression of signaling molecules that block a Wnt5a autoregulatory loop in the perichondrium.

Overexpression of transcription factor FoxA2 in the developing skeleton causes an enlargement of the cartilage hypertrophic zone, but it does not trigger ectopic differentiation in immature chondrocytes.

We previously found that FoxA factors are necessary for chondrocyte differentiation. To investigate whether FoxA factors alone are sufficient to drive chondrocyte hypertrophy, we build a FoxA2 transgenic mouse in which FoxA2 cDNA is driven by a reiterated Tetracycline Response Element (TRE) and a minimal CMV promoter. This transgenic line was crossed with a col2CRE;Rosa26 mouse line to generate col2CRE;Rosa26;TgFoxA2 mice for inducible expression of FoxA2 in cartilage using doxycycline treatment.

Colchicine protects against cartilage degeneration by inhibiting MMP13 expression via PLC-γ1 phosphorylation.

Objective: Low molecular weight compounds that reduce the expression of MMP13 at the mRNA level might serve as disease-modifying osteoarthritis (OA) drugs (DMOADs). The objective of this study was to identify a candidate DMOAD that targets MMP13 expression.

Design: High-throughput screening was performed to identify compounds that suppress inflammatory cytokine-induced MMP13 expression.

Edoxaban in cardiovascular disease management: Review.

In the past decade, direct oral anticoagulants (DOACs) have transformed the world of anti-thrombotic therapy. Edoxaban is the most recently approved DOAC. Though intended for use primarily in stroke prevention, it has found applications in various other conditions including thromboembolic and peripheral arterial disease.

Closing the contraceptive coverage gap: A multipronged approach to advancing reproductive equity in Illinois.

Despite Illinois' progress in the area of reproductive health, Black, Indigenous, and People of Color, young people, and people with low resources face persistent barriers to high-quality contraceptive care and experience inequities in reproductive health outcomes. Illinois Contraceptive Access Now (ICAN!) is a 5-year initiative that aims to improve the quality and coverage of contraceptive care at community health centers statewide. By leveraging state policies, a robust community health infrastructure, digital innovation, and with a focus on sustainability, ICAN! seeks to cut the "contraceptive coverage gap" in Illinois in half by 2025.

Creb5 establishes the competence for Prg4 expression in articular cartilage.

A hallmark of cells comprising the superficial zone of articular cartilage is their expression of lubricin, encoded by the Prg4 gene, that lubricates the joint and protects against the development of arthritis. Here, we identify Creb5 as a transcription factor that is specifically expressed in superficial zone articular chondrocytes and is required for TGF-β and EGFR signaling to induce Prg4 expression. Notably, forced expression of Creb5 in chondrocytes derived from the deep zone of the articular cartilage confers the competence for TGF-β and EGFR signals to induce Prg4 expression.

Rivaroxaban: Expanded Role in Cardiovascular Disease Management-A Literature Review.

Direct oral anticoagulants (DOACs) are widely used for the prevention of stroke in nonvalvular atrial fibrillation, treatment of deep venous thrombosis and pulmonary embolism, and as prophylaxis after hip and knee surgery after approval by the Food and Drug Administration. In the last decade, DOACs were studied for various indications; this review is focused on rivaroxaban, a factor Xa inhibitor, which is used in an expanded evidence-based fashion for coronary artery disease, peripheral artery disease, heart failure, malignancy, and prophylaxis of deep venous thrombosis in acute medical illnesses.

PTHrP targets HDAC4 and HDAC5 to repress chondrocyte hypertrophy.

During endochondral bone formation, chondrocyte hypertrophy represents a crucial turning point from chondrocyte differentiation to bone formation. Both parathyroid hormone-related protein (PTHrP) and histone deacetylase 4 (HDAC4) inhibit chondrocyte hypertrophy. Using multiple mouse genetics models, we demonstrate in vivo that HDAC4 is required for the effects of PTHrP on chondrocyte differentiation.

Finding MyoD and lessons learned along the way.

In 1987, Robert Davis, Hal Weintraub and I reported the identification of MyoD, a transcription factor that could reprogram fibroblasts into skeletal muscle cells. In this recollection, I both summarize the prior work of Helen Blau, Woody Wright, Peter Jones and Charlie Emerson that inspired my entry into this field, and the subsequent events that led to finding MyoD. Lastly, I highlight some of the principles in developmental biology that have emerged during the past 30 years, which are particularly relevant to skeletal muscle biology.

Superficial cells are self-renewing chondrocyte progenitors, which form the articular cartilage in juvenile mice.

Articular cartilage has little regenerative capacity. Recently, genetic lineage tracing experiments have revealed chondrocyte progenitors at the articular surface. We further characterized these progenitors by using genetic approaches.

Composite outcomes in 2.25-mm drug eluting stents: a systematic review.

Background: Coronary atherosclerosis often involves small-caliber coronaries, yet the safety and efficacy of 2.25-mm DES have been poorly defined, with a general lack of separation of 2.25 with 2.

A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation.

Decades of work have identified the signaling pathways that regulate the differentiation of chondrocytes during bone formation, from their initial induction from mesenchymal progenitor cells to their terminal maturation into hypertrophic chondrocytes. Here, we review how multiple signaling molecules, mechanical signals and morphological cell features are integrated to activate a set of key transcription factors that determine and regulate the genetic program that induces chondrogenesis and chondrocyte differentiation. Moreover, we describe recent findings regarding the roles of several signaling pathways in modulating the proliferation and maturation of chondrocytes in the growth plate, which is the 'engine' of bone elongation.

Identification of a Prg4-expressing articular cartilage progenitor cell population in mice.

Objective: To generate knockin mice that express a tamoxifen-inducible Cre recombinase from the Prg4 locus (Prg4(GFPCreERt2) mice) and to use these animals to fate-map the progeny of Prg4-positive articular cartilage cells at various ages.

Methods: We crossed Prg4(GFPCreERt2) mice with Rosa26(floxlacZ) or Rosa26(mTmG) reporter strains, admin-istered tamoxifen to the double heterozygous offspring at different ages, and assayed Cre-mediated recom-bination by histochemistry and/or fluorescence microscopy.

Results: In 1-month-old mice, the expression of the Prg4(GFPCreERt2) allele mirrored the expression of endogenous Prg4 and, when tamoxifen was admin-istered for 10 days, caused Cre-mediated recombination in ∼70% of the superficial-most chondrocytes.

BMP-mediated induction of GATA4/5/6 blocks somitic responsiveness to SHH.

The relative timing of SHH and BMP signals controls whether presomitic mesoderm (PSM) cells will adopt either a chondrogenic or lateral plate mesoderm fate. Here we document that SHH-mediated induction of Nkx3.2 maintains the competence of somitic cells to initiate chondrogenesis in response to subsequent BMP signals by repressing BMP-dependent induction of GATA genes.

Fibroblast growth factor maintains chondrogenic potential of limb bud mesenchymal cells by modulating DNMT3A recruitment.

The formation of cartilage is restricted to the core of the limb bud mesenchyme by ectodermal Wnts, which can irreversibly silence expression of the prochondrogenic transcription factor Sox9. In contrast, fibroblast growth factor (FGF) signals from the apical ectodermal ridge maintain the competence of chondrogenic precursors to undergo chondrogenesis once these cells go out of the range of ectodermal Wnt signals. We have found that Wnt signals induce both a repressive chromatin mark (H3K27me3) and DNA methylation over the Sox9 promoter and that Wnt-induced irreversible silencing of the Sox9 gene requires DNA methylation of this locus, which is specifically countered by FGF signals.

Mechanical motion promotes expression of Prg4 in articular cartilage via multiple CREB-dependent, fluid flow shear stress-induced signaling pathways.

Lubricin is a secreted proteoglycan encoded by the Prg4 locus that is abundantly expressed by superficial zone articular chondrocytes and has been noted to both be sensitive to mechanical loading and protect against the development of osteoarthritis. In this study, we document that running induces maximal expression of Prg4 in the superficial zone of knee joint articular cartilage in a COX-2-dependent fashion, which correlates with augmented levels of phospho-S133 CREB and increased nuclear localization of CREB-regulated transcriptional coactivators (CRTCs) in this tissue. Furthermore, we found that fluid flow shear stress (FFSS) increases secretion of extracellular PGE2, PTHrP, and ATP (by epiphyseal chondrocytes), which together engage both PKA- and Ca(++)-regulated signaling pathways that work in combination to promote CREB-dependent induction of Prg4, specifically in superficial zone articular chondrocytes.

GATA6 is a crucial regulator of Shh in the limb bud.

In the limb bud, patterning along the anterior-posterior (A-P) axis is controlled by Sonic Hedgehog (Shh), a signaling molecule secreted by the "Zone of Polarizing Activity", an organizer tissue located in the posterior margin of the limb bud. We have found that the transcription factors GATA4 and GATA6, which are key regulators of cell identity, are expressed in an anterior to posterior gradient in the early limb bud, raising the possibility that GATA transcription factors may play an additional role in patterning this tissue. While both GATA4 and GATA6 are expressed in an A-P gradient in the forelimb buds, the hindlimb buds principally express GATA6 in an A-P gradient.

Evolutionary conservation of Nkx2.5 autoregulation in the second heart field.

The cardiac homeobox gene Nkx2.5 plays a key and dosage-sensitive role in the differentiation of outflow tract and right ventricle from progenitors of the second heart field (SHF) and Nkx2.5 mutation is strongly associated with human outflow tract congenital heart disease (OFT CHD).

FoxA family members are crucial regulators of the hypertrophic chondrocyte differentiation program.

During endochondral ossification, small, immature chondrocytes enlarge to form hypertrophic chondrocytes, which express collagen X. In this work, we demonstrate that FoxA factors are induced during chondrogenesis, bind to conserved binding sites in the collagen X enhancer, and can promote the expression of a collagen X-luciferase reporter in both chondrocytes and fibroblasts. In addition, we demonstrate by both gain- and loss-of-function analyses that FoxA factors play a crucial role in driving the expression of both endogenous collagen X and other hypertrophic chondrocyte-specific genes.