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First published online July 24, 2009
doi: 10.1242/10.1242/dev.038505

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Conditional inactivation of Has2 reveals a crucial role for hyaluronan in skeletal growth, patterning, chondrocyte maturation and joint formation in the developing limb

Kazu Matsumoto^1,*, Yingcui Li^2,*, Caroline Jakuba², Yoshinori Sugiyama^1,3, Tetsuya Sayo³, Misako Okuno¹, Caroline N. Dealy², Bryan P. Toole⁴, Junji Takeda⁵, Yu Yamaguchi^1, and Robert A. Kosher^2,

¹ Sanford Children's Health Research Center, Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
² Center for Regenerative Medicine and Skeletal Development, Department of Orthopaedic Surgery and University of Connecticut Stem Cell Institute, University of Connecticut Health Center, Farmington, CT 06030, USA.
³ Basic Research Laboratory, Kanebo Cosmetics, Odawara 250-0002, Japan.
⁴ Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, SC 29425, USA.
⁵ Department of Social and Environmental Medicine, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.

Authors for correspondence (e-mails: yyamaguchi{at}burnham.org; rakosher{at}snet.net)

Accepted 9 June 2009

The glycosaminoglycan hyaluronan (HA) is a structural component of extracellular matrices and also interacts with cell surface receptors to directly influence cell behavior. To explore functions of HA in limb skeletal development, we conditionally inactivated the gene for HA synthase 2, Has2, in limb bud mesoderm using mice that harbor a floxed allele of Has2 and mice carrying a limb mesoderm-specific Prx1-Cre transgene. The skeletal elements of Has2-deficient limbs are severely shortened, indicating that HA is essential for normal longitudinal growth of all limb skeletal elements. Proximal phalanges are duplicated in Has2 mutant limbs indicating an involvement of HA in patterning specific portions of the digits. The growth plates of Has2-deficient skeletal elements are severely abnormal and disorganized, with a decrease in the deposition of aggrecan in the matrix and a disruption in normal columnar cellular relationships. Furthermore, there is a striking reduction in the number of hypertrophic chondrocytes and in the expression domains of markers of hypertrophic differentiation in the mutant growth plates, indicating that HA is necessary for the normal progression of chondrocyte maturation. In addition, secondary ossification centers do not form in the central regions of Has2 mutant growth plates owing to a failure of hypertrophic differentiation. In addition to skeletal defects, the formation of synovial joint cavities is defective in Has2-deficient limbs. Taken together, our results demonstrate that HA has a crucial role in skeletal growth, patterning, chondrocyte maturation and synovial joint formation in the developing limb.

Key words: Hyaluronan, Has2, Chondrocyte maturation, Joint development, Skeletal development, Limb development, Mouse

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