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      Multiple Phases of Chondrocyte Enlargement Underlie Differences in Skeletal Proportions

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          Abstract

          Even a casual pass through the great halls of mammals in the world’s natural history museums highlights the wide diversity of skeletal proportions that allow us to distinguish between species even when reduced to their calcified components. Similarly each individual is comprised of a variety of bones of differing lengths. The largest contribution to the lengthening of a skeletal element, and to the differential elongation of elements, comes from a dramatic increase in the volume of hypertrophic chondrocytes in the growth plate as they undergo terminal differentiation 17 . Despite this recognized importance, the mechanisms of chondrocyte volume enlargement have remained a mystery 811 . Here we use quantitative phase microscopy 12 to show that chondrocytes undergo three distinct phases of volume increase, including a phase of massive cell swelling in which the cellular dry mass is significantly diluted. In light of the tight fluid regulatory mechanisms known to control volume in many cell types 13 , this stands as a remarkable mechanism for increasing cell size and regulating growth rate. It is, however, the duration of the final phase of volume enlargement by proportional dry mass increase at low density that varies most between rapidly and slowly elongating growth plates. Moreover, we find that this third phase is locally regulated through an Insulin-like Growth Factor-dependent mechanism. This study provides a framework for understanding how skeletal size is regulated and for exploring how cells sense, modify, and establish a volume set point.

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          Most cited references28

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          Physiology of cell volume regulation in vertebrates.

          The ability to control cell volume is pivotal for cell function. Cell volume perturbation elicits a wide array of signaling events, leading to protective (e.g., cytoskeletal rearrangement) and adaptive (e.g., altered expression of osmolyte transporters and heat shock proteins) measures and, in most cases, activation of volume regulatory osmolyte transport. After acute swelling, cell volume is regulated by the process of regulatory volume decrease (RVD), which involves the activation of KCl cotransport and of channels mediating K(+), Cl(-), and taurine efflux. Conversely, after acute shrinkage, cell volume is regulated by the process of regulatory volume increase (RVI), which is mediated primarily by Na(+)/H(+) exchange, Na(+)-K(+)-2Cl(-) cotransport, and Na(+) channels. Here, we review in detail the current knowledge regarding the molecular identity of these transport pathways and their regulation by, e.g., membrane deformation, ionic strength, Ca(2+), protein kinases and phosphatases, cytoskeletal elements, GTP binding proteins, lipid mediators, and reactive oxygen species, upon changes in cell volume. We also discuss the nature of the upstream elements in volume sensing in vertebrate organisms. Importantly, cell volume impacts on a wide array of physiological processes, including transepithelial transport; cell migration, proliferation, and death; and changes in cell volume function as specific signals regulating these processes. A discussion of this issue concludes the review.
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            Normal growth and development in the absence of hepatic insulin-like growth factor I.

            The somatomedin hypothesis proposed that insulin-like growth factor I (IGF-I) was a hepatically derived circulating mediator of growth hormone and is a crucial factor for postnatal growth and development. To reassess this hypothesis, we have used the Cre/loxP recombination system to delete the igf1 gene exclusively in the liver. igf1 gene deletion in the liver abrogated expression of igf1 mRNA and caused a dramatic reduction in circulating IGF-I levels. However, growth as determined by body weight, body length, and femoral length did not differ from wild-type littermates. Although our model proves that hepatic IGF-I is indeed the major contributor to circulating IGF-I levels in mice it challenges the concept that circulating IGF-I is crucial for normal postnatal growth. Rather, our model provides direct evidence for the importance of the autocrine/paracrine role of IGF-I.
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              Diffraction phase microscopy for quantifying cell structure and dynamics.

              We have developed diffraction phase microscopy as a new technique for quantitative phase imaging of biological structures. The method combines the principles of common path interferometry and single-shot phase imaging and is characterized by subnanometer path-length stability and millisecond-scale acquisition time. The potential of the technique for quantifying nanoscale motions in live cells is demonstrated by experiments on red blood cells.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                8 February 2013
                13 March 2013
                21 March 2013
                21 September 2013
                : 495
                : 7441
                : 375-378
                Affiliations
                [1 ]Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
                [2 ]Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
                [3 ]George R. Harrison Spectroscopy Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
                Author notes
                []Author for correspondence: kcooper@ 123456genetics.med.harvard.edu
                [*]

                These authors contributed equally to this work.

                Article
                NIHMS440348
                10.1038/nature11940
                3606657
                23485973
                4f454d55-5902-4a1c-b760-78c5cb84a54d

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: P01 DK056246 || DK
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