Scholars@Duke
Holly Leddy

Holly Leddy

Research Scientist
Pratt School of Engineering
Box 90271, Smif, Durham, NC 27708
1587 Fitzpatrick CIEMAS, Duke University, Durham, NC 27708

Selected Publications

TRPV4-mediated calcium signaling in mesenchymal stem cells regulates aligned collagen matrix formation and vinculin tension.

Journal Article Proc Natl Acad Sci U S A · February 5, 2019 Featured Publication Microarchitectural cues drive aligned fibrillar collagen deposition in vivo and in biomaterial scaffolds, but the cell-signaling events that underlie this process are not well understood. Utilizing a multicellular patterning model system that allows for ob ... Full text Link to item Cite

Type VI Collagen Regulates Pericellular Matrix Properties, Chondrocyte Swelling, and Mechanotransduction in Mouse Articular Cartilage.

Journal Article Arthritis Rheumatol · May 2015 Featured Publication OBJECTIVE: Mechanical factors play a critical role in the physiology and pathology of articular cartilage, although the mechanisms of mechanical signal transduction are not fully understood. We undertook this study to test the hypothesis that type VI colla ... Full text Link to item Cite

TRPV4 as a therapeutic target for joint diseases.

Journal Article Naunyn Schmiedebergs Arch Pharmacol · April 2015 Biomechanical factors play a critical role in regulating the physiology as well as the pathology of multiple joint tissues and have been implicated in the pathogenesis of osteoarthritis. Therefore, the mechanisms by which cells sense and respond to mechani ... Full text Link to item Cite

Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage.

Journal Article Proc Natl Acad Sci U S A · November 25, 2014 Featured Publication Diarthrodial joints are essential for load bearing and locomotion. Physiologically, articular cartilage sustains millions of cycles of mechanical loading. Chondrocytes, the cells in cartilage, regulate their metabolic activities in response to mechanical l ... Full text Open Access Link to item Cite

The mechanobiology of articular cartilage: bearing the burden of osteoarthritis.

Journal Article Curr Rheumatol Rep · October 2014 Articular cartilage injuries and degenerative joint diseases are responsible for progressive pain and disability in millions of people worldwide, yet there is currently no treatment available to restore full joint functionality. As the tissue functions und ... Full text Link to item Cite

Follistatin in chondrocytes: the link between TRPV4 channelopathies and skeletal malformations.

Journal Article FASEB J · June 2014 Featured Publication Point mutations in the calcium-permeable TRPV4 ion channel have been identified as the cause of autosomal-dominant human motor neuropathies, arthropathies, and skeletal malformations of varying severity. The objective of this study was to determine the mec ... Full text Link to item Cite

TRPV4-mediated mechanotransduction regulates the metabolic response of chondrocytes to dynamic loading.

Journal Article Proc Natl Acad Sci U S A · January 28, 2014 Featured Publication Mechanical loading of joints plays a critical role in maintaining the health and function of articular cartilage. The mechanism(s) of chondrocyte mechanotransduction are not fully understood, but could provide important insights into new physical or pharma ... Full text Link to item Cite

Unraveling the mechanism by which TRPV4 mutations cause skeletal dysplasias.

Journal Article Rare Dis · 2014 Transient Receptor Potential Vanilloid 4 (TRPV4) is a mechano- and osmosensitive cation channel that is highly expressed in chondrocytes, the cells in cartilage. A large number of mutations in TRPV4 have been linked to skeletal dysplasias, and the goal of ... Full text Link to item Cite

High body mass index is associated with increased diurnal strains in the articular cartilage of the knee.

Journal Article Arthritis Rheum · October 2013 Featured Publication OBJECTIVE: Obesity is an important risk factor for osteoarthritis (OA) and is associated with changes in both the biomechanical and inflammatory environments within the joint. However, the relationship between obesity and cartilage deformation is not fully ... Full text Link to item Cite

Synovial fluid concentrations and relative potency of interleukin-1 alpha and beta in cartilage and meniscus degradation.

Journal Article J Orthop Res · July 2013 Cartilage degeneration with osteoarthritis (OA) is believed to involve the activities of interleukin-1 (IL-1), which exists as alpha and beta isoforms. The goal of this study was to measure the concentrations of both isoforms of IL-1 in the synovial fluid ... Full text Link to item Cite

Diurnal variations in articular cartilage thickness and strain in the human knee.

Journal Article J Biomech · February 1, 2013 Due to the biphasic viscoelastic nature of cartilage, joint loading may result in deformations that require times on the order of hours to fully recover. Thus, cartilaginous tissues may exhibit cumulative strain over the course of each day. The goal of thi ... Full text Link to item Cite

Effects of myocardial infarction on the distribution and transport of nutrients and oxygen in porcine myocardium.

Journal Article Journal of biomechanical engineering · October 2012 One of the primary limitations of cell therapy for myocardial infarction is the low survival of transplanted cells, with a loss of up to 80% of cells within 3 days of delivery. The aims of this study were to investigate the distribution of nutrients and ox ... Full text Cite

Altered trabecular bone structure and delayed cartilage degeneration in the knees of collagen VI null mice.

Journal Article PloS one · January 2012 Mutation or loss of collagen VI has been linked to a variety of musculoskeletal abnormalities, particularly muscular dystrophies, tissue ossification and/or fibrosis, and hip osteoarthritis. However, the role of collagen VI in bone and cartilage structure ... Full text Open Access Cite

Osmotic stress alters chromatin condensation and nucleocytoplasmic transport.

Journal Article Biochemical and biophysical research communications · May 2011 Osmotic stress is a potent regulator of biological function in many cell types, but its mechanism of action is only partially understood. In this study, we examined whether changes in extracellular osmolality can alter chromatin condensation and the rate o ... Full text Cite

Transient receptor potential vanilloid 4: The sixth sense of the musculoskeletal system?

Journal Article Ann N Y Acad Sci · March 2010 The critical discovery in the past two decades of the transient receptor potential (TRP) superfamily of ion channels has revealed the potential mechanisms by which cells sense diverse stimuli beyond the prototypical "five senses," identifying ion channels ... Full text Link to item Cite

Functional characterization of TRPV4 as an osmotically sensitive ion channel in porcine articular chondrocytes.

Journal Article Arthritis Rheum · October 2009 Featured Publication OBJECTIVE: Transient receptor potential vanilloid 4 (TRPV4) is a Ca(2+)-permeable channel that can be gated by tonicity (osmolarity) and mechanical stimuli. Chondrocytes, the cells in cartilage, respond to their osmotic and mechanical environments; however ... Full text Link to item Cite

Microscale diffusion properties of the cartilage pericellular matrix measured using 3D scanning microphotolysis.

Journal Article Journal of biomechanical engineering · December 2008 Chondrocytes, the cells in articular cartilage, are enclosed within a pericellular matrix (PCM) whose composition and structure differ from those of the extracellular matrix (ECM). Since the PCM surrounds each cell, molecules that interact with the chondro ... Full text Cite

Site-specific effects of compression on macromolecular diffusion in articular cartilage.

Journal Article Biophysical journal · November 2008 Featured Publication Articular cartilage is the connective tissue that lines joints and provides a smooth surface for joint motion. Because cartilage is avascular, molecular transport occurs primarily via diffusion or convection, and cartilage matrix structure and composition ... Full text Cite

Zonal changes in the three-dimensional morphology of the chondron under compression: The relationship among cellular, pericellular, and extracellular deformation in articular cartilage

Journal Article Journal Of Biomechanics · 2007 The pericellular matrix (PCM) is a narrow region of tissue that completely surrounds chondrocytes in articular cartilage. Previous theoretical models of the "chondron" (the PCM with enclosed cells) suggest that the structure and properties of the PCM may s ... Cite

Diffusional anisotropy in collagenous tissues: fluorescence imaging of continuous point photobleaching.

Journal Article Biophysical journal · July 2006 Molecular transport in avascular collagenous tissues such as articular cartilage occurs primarily via diffusion. The presence of ordered structures in the extracellular matrix may influence the local transport of macromolecules, leading to anisotropic diff ... Full text Cite

Composition and transport properties of human ankle and knee cartilage.

Journal Article J Orthop Res · February 2006 The incidence of osteoarthritis is significantly higher in the knee as compared to the ankle, suggesting that differences in the properties of cartilage from these joints may contribute to the development of osteoarthritis. As an avascular tissue, articula ... Full text Link to item Cite

Adjacent tissues (cartilage, bone) affect the functional integration of engineered calf cartilage in vitro.

Journal Article Osteoarthritis and cartilage · February 2005 ObjectiveAn in vitro model was used to test the hypothesis that culture time and adjacent tissue structure and composition affected chondrogenesis and integrative repair in engineered cartilage.MethodEngineered constructs made of bovine c ... Full text Cite

Molecular diffusion in tissue-engineered cartilage constructs: effects of scaffold material, time, and culture conditions.

Journal Article Journal of biomedical materials research. Part B, Applied biomaterials · August 2004 Diffusion is likely to be the primary mechanism for macromolecular transport in tissue-engineered cartilage, and providing an adequate nutrient supply via diffusion may be necessary for cell proliferation and extracellular matrix production. The goal of th ... Full text Cite

Chondrogenic differentiation of adipose-derived adult stem cells in agarose, alginate, and gelatin scaffolds.

Journal Article Biomaterials · July 2004 The differentiation and growth of adult stem cells within engineered tissue constructs are hypothesized to be influenced by cell-biomaterial interactions. In this study, we compared the chondrogenic differentiation of human adipose-derived adult stem (hADA ... Full text Cite

Adipose-derived adult stem cells for cartilage tissue engineering.

Journal Article Biorheology · January 2004 Tissue engineering is a promising therapeutic approach that uses combinations of implanted cells, biomaterial scaffolds, and biologically active molecules to repair or regenerate damaged or diseased tissues. Many diverse and increasingly complex approaches ... Cite

Site-specific molecular diffusion in articular cartilage measured using fluorescence recovery after photobleaching.

Journal Article Annals of biomedical engineering · July 2003 Diffusive transport of solutes is critical to the normal function of articular cartilage. The diffusion of macromolecules through cartilage may be affected by the local composition and structure, which vary with depth from the tissue surface. We hypothesiz ... Full text Cite

Sutural loosening and skeletal flexibility during growth: determination of drop-like shapes in sea urchins.

Journal Article Proceedings. Biological sciences · February 2002 The shape of sea urchins may be determined mechanically by patterns of force analogous to those that determine the shape of a water droplet. This mechanical analogy implies skeletal flexibility at the time of growth. Although comprised of many rigid calcit ... Full text Cite

Surface protein characterization of human adipose tissue-derived stromal cells.

Journal Article J Cell Physiol · October 2001 Human bone marrow stromal cells are a multipotent population of cells capable of differentiating into a number of mesodermal lineages as well as supporting hematopoeisis. Their distinct protein and gene expression phenotype is well characterized in the lit ... Full text Link to item Cite

Walking versus breathing: mechanical differentiation of sea urchin podia corresponds to functional specialization.

Journal Article The Biological bulletin · February 2000 The podia of sea urchins function in locomotion, adhesion, feeding, and respiration; but different podia on a single urchin are often specialized to one or more of these tasks. We examined the morphology and material properties of podia of the green sea ur ... Full text Cite