Conditional inactivation ofHas2reveals a crucial role for hyaluronan in skeletal growth, patterning, chondrocyte maturation and joint formation in the developing limb

Abstract

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.

Bone Morphogenic Protein (BMP) Signaling Up-regulates Neutral Sphingomyelinase 2 to Suppress Chondrocyte Maturation via the Akt Protein Signaling Pathway as a Negative Feedback Mechanism

“…It is produced in the plasma membrane by three hyaluronan synthases (Has1-3); Has2 is the crucial hyaluronan synthase involved in the endochondral ossification process (53). The Akt-rpS6 pathway is important in the expression of Has2 in MCF-7 breast cancer cells (64), although nSMase2 suppresses production of Has2 via inactivation of Akt in mouse dermal fibroblasts (50).…”

Hyaluronan is required for cranial neural crest cells migration and craniofacial development

“…In particular, the glycosaminoglycan hyaluronan, one of the key components of the vertebrate extracellular matrix, is essential in dynamic cellular systems such as the developing embryo (Camenish et al, 2000;Toole, 2001;Ori et al, 2006;Li et al, 2007;Matsumoto et al 2009;Tammi et al, 2011), tissue wound repair and regeneration (Jiang et al, 2007;Contreras et al, 2009), inflammation processes (Hascall et al, 2004;Jiang et al, 2011), and tumorigenesis (Toole and Slomiany, 2008;Misra et al, 2011).…”

Low Dose Ultraviolet B Irradiation Increases Hyaluronan Synthesis in Epidermal Keratinocytes via Sequential Induction of Hyaluronan Synthases Has1–3 Mediated by p38 and Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) Signaling*

“…Moreover, it is needed by various cell types for attachment, migration, proliferation, and signaling, and its roles in embryonic development (15,16), inflammation (17,18), and cancer initiation and progression are widely recognized (19,20). In the adult skin, hyaluronan participates in hydration (5), wound healing (21,22), and maintenance of the balance between cell division and differentiation in the epidermis (23).…”