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2011 Annual Meeting Abstracts

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Muenke Mutation causes Accelerated Maturation of Chondrocytes and Precocious Ossification of Basicranial Synchondrosis Cartilage, Leading to Shortening of the Cranial Base and Osteopenia in a FGFR3P244R Knock-in Mouse Model
Bianca C. Chin, M.D1, Jason T. Laurita, MB2, Eiki Koyama, D.D.S, Ph.D3, Scott P. Bartlett, M.D2, Hyun- Duck Nah, D.D.S, Ph.D2.
1University of Pennsylvania, Philadelphia, PA, USA, 2Children's Hospital of Philadelphia, Philadelphia, PA, USA, 3Thomas Jefferson University, Philadelphia, PA, USA.

PURPOSE: Muenke syndrome is an autosomal dominant form of syndromic craniosynostosis caused by a ligand-dependent activating mutation (P250R) in Fibroblast Growth Factor Receptor 3 (FGFR3). The syndrome is primarily characterized by uni-/bi-coronal synostosis with approximately 59% of cases presenting with mid-face hypoplasia, although its presentation can be heterogenous. FGFR3 is a negative regulator of endochondral ossification and is expressed in synchondrosis of the cranial base with the spheno-occiputal (SOS) and presphenoidal synchondrosis (PSS) being the primary centers of postnatal cranial base growth and midface development. While other activating FGFR3 mutations have been shown to stunt growth of basicranial synchondrosis and epiphyseal growth cartilage, little is known about the consequences of Muenke mutation on growth and development of basicranial cartilage. We hypothesize that Muenke mutation induces precocious maturation and ossification of basicranial synchondrosis cartilage leading to cranial base deficiency and associated midface hypoplasia.
METHODS:The FgfR3P244R mouse model analogous to the P250R mutation in human FGFR3 of Muenke Syndrome was utilized. Homozygous (n=26), heterozygous (n=20) and wild type (WT, n=20) littermates were sacrificed postnatal days (P) 7, 21, 35 and 6-12 months. Skulls were analyzed by micro-CT to grade of basicranial synchondrosis closure and 3-D craniomorphometry. Skulls were processed for histology and in-situ hybridization evaluating chondrocyte differentiation stage-specific genes (Sox 9, Col IIB, CTGF, Ihh and ColX), genetic markers of early osteogenic differentiation (Col 1, Osterix, and Osteopontin) and chondrocyte to bone transition (MMP9 and MMP13).
RESULTS:Craniofacial abnormalities including premature fusion of premaxillary suture, incisor malocclusion and snout deviation were identified as early as P7 in mutant mice. Micro-CT analysis demonstrated premature ossification of the PSS by P21 while WT remained patent into adulthood (>8 weeks) and skull bones appeared osteopenic. Histology showed cellular disorganization of basicranial synchondrosis with loss of characteristic growth plate zones, significantly less resting and proliferating chondrocytes, premature appearance of secondary ossification center and abnormal perichondrial bony bridging. There was synchondrosis shortening, abrupt transition from cartilage to marrow with reduction in primary spongiosa and endochondral bone. In-situ hybridization revealed reduced number of chondrocytes expressing chondrocyte differentiation markers (Sox9, Col IIB, Col X), and an abnormal population of pre-hypertrophic chondrocytes in the resting zone area expressing CTGF but not ColX. Ihh-PTHrP mediated chondrocyte proliferation was decreased. There was precocious appearance of genetic markers of early osteogenic differentiation (Col I, Osteopontin, Osterix) in the area of the perichondrial bony bridge instead of being confined to the osteogenic front as in the wild type. Decreased expression of genes important for cartilage to bone transition (MMP9, MMP13) and increased apoptosis was seen in the primary spongiosa contributing to the osteopenia observed in Muenke syndrome.
CONCLUSION:Based on the mouse model, we have demonstrated that Muenke mutation does cause cranial base deficiency likely attributable to accelerated maturation with decreased proliferation of basicranial synchondrosis chondrocytes and the tendency to premature ossification. Although there is precocious bone formation, the primary spongiosa is an unsuitable niche for osteoblast progenitors indicated by increased apoptosis resulting in osteopenia.

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