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The Cranial Base in Craniofacial Development: a Gene Therapy Study
S. Kyrkanides1,2,*,
P. Kambylafkas1,
J.H. Miller1,
R.H. Tallents1 and
J.E. Puzas3
1 Departments of Dentistry,
2 Neurobiology & Anatomy, and
3 Department of Orthopedics and Center for Musculo-skeletal Research, School of Medicine and Dentistry, University of Rochester Medical Center, 625 Elmwood Ave., Rochester NY 14620, USA
Correspondence: * corresponding author, stephanos_kyrkanides{at}urmc.rochester.edu
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ABSTRACT
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The etiology of midface retrusion remains largely unclear. We hypothesized that the cranial base synchondroses play a key role in the development of the craniofacial skeleton in the Sandhoff mouse model. We observed that developmental abnormalities of the cranial base synchondroses involving proliferative chondrocytes are important in craniofacial growth and development. Neonatal restitution of β-hexosaminidase in mutant mice by gene therapy successfully ameliorated the attendant skeletal defects and restored craniofacial morphology in vivo, suggesting this as a critical temporal window in craniofacial development. Analysis of our data implicates parathyroid-related peptide (PTHrP) and cyclo-oxygenase-2 (COX-2) as possible factors underlying the development of the aforementioned skeletal defects. Hence, timely restitution of a genetic deficiency or, alternatively, the restoration of PTHrP or cyclo-oxygenase activity by the administration of PTH and/or non-steroidal anti-inflammatory drugs or COX-2 selective inhibitors to affected individuals may prove beneficial in the management of midface retrusion.
Key Words: maxilla • skull base • cartilage • growth plate • lysosomal storage diseases • Sandhoff disease • maxillofacial development
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INTRODUCTION
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The spheno-occipital synchondrosis (SOS) is located between the sphenoid and occipital bones, and is the only growth plate in the cranial base that remains anabolically active up to adolescent age in humans (Mao and Nah, 2004). The SOS appears primarily responsible for the growth of the cranial base and, ultimately, via multiple articulations among craniofacial bones, of all facial skeletal structures, such as the maxilla and mandible (Baume, 1970; Mao and Nah, 2004). Although craniofacial development begins early in embryogenesis, a large portion of bone growth occurs post-natally. Anthropometric studies (reviewed in Gorlin et al., 1990) revealed that more than 39% of craniofacial growth occurs in the sagittal plane, 37% in the transverse plane, and 31% in the vertical plane. The anterior cranial base attains 55% of its total growth post-natally. Premature arrest of the SOS may lead to craniofacial abnormalities, including achondroplasia, Apert syndrome, cleidocranial dysplasia, Crouzon syndrome, and mandibulofacial dysostosis (Horowitz, 1981; Peterson-Falzone and Figueroa, 1989; Jensen and Kreiborg, 1993; Kjaer et al., 2001). Microscopically, the SOS is comprised of the equivalent of two apparently typical appendicular growth plates merged at their reserve zones, and exhibits bidirectional growth during endochondral ossification (Mao and Nah, 2004; Opperman et al., 2005). Organ culture studies show that the cranial base synchondroses have independent growth potential (Gakunga et al., 2000; Shum et al., 2003), suggestive of a growth center (Baume, 1970; van Limborgh, 1972; Mao and Nah, 2004), although their growth can be influenced by short cyclical mechanical forces (Wang and Mao, 2002a,b).
We hypothesized that factors capable of disturbing the development of the cranial base synchondroses can potentially lead to midface retrusion. Limited information is available, however, on the underlying etiology of midface hypoplasia. The goal of this study was to examine the mechanism through which, and the timing during which, midface hypoplasia develops in relation to cranial base development. To this end, we used the HexB–/–mouse (Sango et al., 1995) as a model of craniofacial dysplasia (Suzuki et al., 1997), since it displays midface retrusion similar to that seen in persons with Sandhoff disease. We evaluated craniofacial growth and development in the HexB–/– mouse at the anatomical, cellular, and molecular levels. Furthermore, neonatal restitution of β-hexosaminidase in the HexB–/– mouse confirmed the post-natal developmental stage during which chondrocyte maturational abnormalities can impair craniofacial skeletogenesis.
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MATERIALS & METHODS
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Animals
The HexB–/– mice were originally developed, with the use of 129S4 ES cells, in C57BL/6 embryos and were subsequently maintained on a 129S4 background strain (Sango et al., 1995). In total, 31 mice were used in this study: HexB–/– (N = 16), HexB+/– (N = 6), and wild-type (N = 9) mice on the 129S4 background strain were produced as previously described (Kyrkanides et al., 2005). HexB+/– breeder pairs on the 129S4 background (provided by Dr. Richard Proia, NIDDK/NIH, Bethesda, MD, USA) were mated to produce homozygous HexB–/– mice. All experimental protocols involving animals were approved by the University Committee on Animal Resources and performed in AAALAC-accredited specific pathogen-free facilities at the University of Rochester Medical Center. HexB–/–neonates were injected intraperitoneally at post-natal day P4 with 107 infectious FIV(HEX) particles in 100 µL normal saline (Kyrkanides et al., 2003a,b, 2005).
Cephalometric Radiography
Cephalometric analysis provided quantitative information on the growth of the craniofacial skeleton. In brief, the animals were anesthetized by ketamine (40 mg/Kg) via intraperitoneal injection, and immobilized on a customized cephalostat, with the cranial mid-sagittal plane positioned parallel to the cephalometric film cassette. Radiographs were obtained by means of a long-cone x-ray machine (Oralix 65, Philips Medical Systems, Bothell, WA, USA) at 6 mA, 25 KVP, and an exposure time of 2.5 sec. The following points were traced on the cephalometric radiographs: Ba, Basion, defined as the most posterior-inferior cephalometric point of the basiocciput; Rh, Rhinion, the most anterior cephalometric point of the nasal bone; and Na, Nasion, the cephalometric point between the nasal bone and the frontal bone (Fujita et al., 2004). The cranial and nasomaxillary measurements in each animal were normalized in reference to the length of the mandibular corpus, defined as the distance between gonion (Go) and menton (Me). Using this method, we examined craniofacial morphology in mice at 8 and 16 wks of age. Statistical analysis was undertaken by analysis of variance methods, with  = 0.05, and Tukey’s post hoc analysis. All landmark identifications and measurements were performed by one investigator (PK), and the intra-examiner reliability was calculated by correlation coefficient on 10 radiographs as r > 0.9 prior to the commencement of the study. In addition, since the cranial base synchondroses and long bone growth plates share similar endochondral bone growth mechanisms, the long bone growth plates were also included in our study for comparison.
Histological Studies
Histological analysis of long bone growth plates and cranial base synchondroses was performed in samples obtained from 16-week-old HexB–/– mice. Under surgical anesthesia (ketamine 40 mg/Kg plus pentobarbital 100 mg/Kg), the mice were transcardially perfused with 100 mL of 4% paraformaldehyde in phosphate-buffered saline. Subsequently, the cranial bases were dissected, defleshed, and decalcified by immersion in an EDTA (ethylenediamine tetraacetic acid) solution for 7 days at 4°C under constant agitation. The tissues were then processed on a RHS-1 microwave tissue processor (Milestone Medical, San Marcos, CA, USA), after which the samples were embedded in paraffin. Tissues were cut on a microtome as 3-µm-thick sections, and the presence of cartilage in the synchondroses was detected by Alcian blue-orange G histochemistry.
Immunohistochemical analysis was performed for several antigens. The tissue slides were first deparaffinized in xylene, rehydrated through graded alcohols, and quenched in 3% H2O2 for 20 min. Antigen retrieval was performed in a 10-mM citrate buffer, pH 6.0. For collagen type II (Col-2), the tissue was also digested with pepsin (0.2%). Subsequently, the tissue was blocked with the appropriate primary serum solution, followed by overnight incubation in primary antibody solution at 4°C. The sections were rinsed with PBS and incubated in an appropriate biotinylated secondary antibody solution for 30 min, followed by PBS wash and incubation in horseradish-peroxidase-conjugated streptavidin. AEC was used as the chromagen. Sections were counterstained with hematoxylin, followed by PBS wash, alcohol dehydration, xylene clearing, and cover-slipped permanent mounting media. Specifically, goat anti-Col-2 was purchased from Lab Vision Corp. (Fremont, CA, USA) and used at a 1:40 dilution. Goat anti-parathyroid-related peptide (PTHrP) antibody (dilution 1:40) was purchased from Santa Cruz Biotechnology Inc. (Santa Cruz, CA, USA). The rabbit anti-(murine)COX-2 was purchased from Cayman (Ann Arbor, MI, USA), and the rabbit anti-active p38 antibody from Promega (Madison, WI, USA). Appropriate biotin-conjugated secondary antibodies were purchased from Jackson Immunoresearch (West Grove, PA, USA).
In vitro Studies
The C2C12 cell line, an in vitro model of chondrocyte differentiation and maturation, was purchased from the American Tissue Culture Collection (Manassas, VA, USA) and cultured in DMEM plus 10% normal bovine serum for 4 days as previously described (Katagiri et al., 1994). Cells were treated with BMP-2 (300 ng/mL), BMP-2 plus PGE2 (10–8 M), or BMP-2 plus recombinant IL-1β (10 ng/mL) or BMP-2 plus Butaprost (10–8 M) in the culture medium. At the end of the experiment, cells were fixed with 10% formalin. Alkaline phosphatase expression was evaluated by the BCIP/NBT histochemistry method (Vector Labs, Burlingame, CA, USA). Positively stained cells were counted in 10 random fields at 20X magnification viewed under an inverted Olympus CK41 microscope (Tokyo, Japan).
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RESULTS
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Developmental Abnormalities Present in the SOS of Sandhoff Mice
We first evaluated the spheno-occipital and spheno-ethmoidal synchondroses in the HexB-deficient (HexB–/–) mice at the histological, cellular, and molecular levels. Qualitatively, HexB–/– synchondroses manifested a decrease in extracellular cartilage content and aberrant ectopic bone formation, while maintaining their chondrocyte cell populations (Fig. 1 ). Furthermore, a loss of normal cyto-architecture was evident in the mutant mice, characterized by the absence of chondrocyte column formation in the proliferative zone, and the complete lack of a resting zone (Fig. 1). The HexB–/– femur and tibia presented normal growth plate cyto-architecture and histology (Fig. 1). Changes in the expression of markers associated with skeletogenesis were also observed in the cranial base synchondroses, including a decrease in PTHrP expression (Fig. 1), along with induction of the stress-activated p38 MAK and COX-2 (Fig. 2). Immunohistochemical analysis of Ihh, SOX-9, and VEGF revealed no change in their expression levels (see APPENDIX).
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Figure 1. Cellular organization and chondrocyte maturation are selectively impaired in the cranial base synchondroses. Comparison of histology sections processed for Alcian blue-orange G histochemistry that were harvested from long bone growth plates (tibia) of (A) wild-type, (B) mutant, and (C) FIV(HEX)-treated mice revealed the absence of any histopathology in the long bones of affected mice. These findings were confirmed by immunohistochemical analysis of (D) wild-type, (E) mutant, and (F) FIV(HEX)-treated mice, with antibodies against type 2 collagen. Conversely, we observed significant histopathological differences between (G) wild-type and (H) mutant mice. Representative images are shown here. Specifically, the HexB–/– mice displayed reduced levels of cartilage content (light blue stain) and ectopic bone formation (red stain). There was also loss of chondrocyte column formation that is normally seen in these areas. (I) Neonatal FIV(HEX) gene therapy normalized the cyto-architecture and ameliorated any histopathology at the cranial base synchondroses. These findings were further confirmed by type 2 collagen immunohistochemistry in (J) wild-type, (K) mutant, and (L) FIV(HEX)-treated synchondroses. (M) PTHrP, a known regulator of chondrocyte differentiation and maturation, was absent (N) in HexB–/– synchondroses and was restored in part in (O) the FIV(HEX)-treated mutant mice. Bar = 100 µm.
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Figure 2. COX-2 activation is implicated in abnormal cranial base development. The stress-activated p38 MAK, a known inducer of COX-2, was induced in (A) the proliferative zone chondrocytes of HexB–/– mice, compared with (B) wild-type mice, as assessed by immunofluorescence. The expression of COX-2, a regulator of chondrocyte differentiation and maturation, was also induced in (C) HexB–/– vs. (D) wild-type mice, as detected by immunofluorescence. Nuclear Hoechst staining displays the cell population present in the aforementioned images (A–E; B–F; C–G; D–H). The pertinent histology is depicted (A–I; B–J; C–K; D–L) as captured by light microscopy. Representative images are shown. Bar = 100 µm.
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For quantitative evaluation of the affected craniofacial structures, cephalometric analysis with angular and linear measurements on lateral cephalometric radiographs were obtained from HexB–/–, HexB+/–, and wild-type littermates. Analysis of the data revealed that HexB–/– mice were characterized by shorter nasomaxillary depth (Na-Rh), shorter craniofacial depth (Ba-Rh), and shorter cranial base depth (Ba-Na), compared with HexB+/– and wild-type mice (Fig. 3). Specifically, the Ba-Rh measurements were 84.46 mm (± 2.33), 101.64 mm (± 8.22), 101.11 mm (± 11.16), and 102.31 mm (± 6.84) for the HexB–/–, HexB+/–, wild-type mice, and the FIV(HEX)-treated HexB–/– mice, respectively. The Na-Rh measurements were 80.65 mm (± 6.73), 99.25 mm (± 11.59), 103.3 mm (± 11.42), and 98.50 mm (± 8.25) for the HexB–/–, HexB+/–, wild-type mice, and the FIV(HEX)-treated HexB–/–mice, respectively. The Na-Ba measurements were 73.2 mm (± 3.11), 92.6 mm (± 6.73), 92.38 mm (± 14.55), and 83.23 mm (± 4.51) for the HexB–/–, HexB+/–, wild-type mice, and the FIV(HEX)-treated HexB–/– mice, respectively. For all three measurements, the HexB–/– mice displayed smaller values compared with the other 3 groups at the p < 0.05 level of statistical significance. Interestingly, there were no differences in mandibular size in the animals examined (P > 0.1). Since no differences between the 8- and 16-week time-points were identified, only the 8-week results are shown here. We evaluated overall growth by measuring gross weight on a weekly basis; no differences were noted among the animal groups (P > 0.1). In conclusion, the aforementioned analyses confirmed that the craniofacial skeletal impairment was localized to the animals’ cranial base, the skeletal structure whose growth is dependent upon the development of the spheno-occipital and spheno-ethmoidal synchondroses.
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Figure 3. Craniofacial morphology was evaluated in HexB–/– (N = 6), HexB+/– heterozygotes (N = 6), wild-type (N = 7), and FIV(HEX)-treated HexB–/– mice (N = 10). Lateral cephalometric radiographs of (A) HexB–/–and (B) wild-type mice are shown (arrow points to cranial base). (C) Summary of cephalometric measurements performed in this study. Cephalometric analysis revealed that (D) the Ba-Rh, (E) Na-Rh, and (F) Na-Ba distances were significantly reduced in the HexB–/– mice, compared with HexB+/– and wild-type controls, as well as FIV(HEX)-treated mice. These measurements demonstrate the presence of cranial base and nasomaxillary deficiencies in mice suffering from β-hexosaminidase deficiency. Analysis of the data also showed that neonatal β-hexosaminidase restitution rescued the HexB–/– mice from developing craniofacial dysplasia. Differences among the 4 groups were evaluated by one-way analysis of variance, followed by post hoc analysis by Dunnett’s method. Ba-Rh differences were statistically different at p = 0.00282 (power = 0.8913); for Na-Rh, p = 0.0020 (power = 0.9212); and for Na-Ba, p = 0.0021 (power = 0.91). Mean ± SD. *p < 0.05.
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SOS Defects are Temporally Localized to Neonatal Stages of Development
To determine the developmental window during which β-hexosaminidase deficiency affects chondrocyte maturation, we rescued HexB–/– mice from β-hexosaminidase deficiency at a neonatal stage of development. To this end, we used a method previously developed in our laboratory (Kyrkanides et al., 2005), which involved the systemic transfer of a therapeutic gene by the recombinant feline immunodeficiency virus FIV(Hex). Histological analysis of the cranial base synchondroses revealed normalization of the cyto-architecture in the cranial base synchondroses of the mice at 4 mos of age (Fig. 1 ). Immunohistochemical analysis of bone markers revealed that neonatal FIV(Hex) treatment in HexB–/– neonates restored the expression of PTHrP and attenuated the expression pattern of Col-2 (Fig. 1). Interestingly, we did not observe the presence of the therapeutic gene in the growth plate chondrocyte (see APPENDIX). These data were further confirmed by cephalometric measurements, whereby FIV(Hex)-treated HexB–/– neonates displayed near-normal craniofacial form at 2 and 4 mos after treatment (Fig. 3).
Role of the COX-2/PGE2 Pathway
We began exploring the possible mechanisms underlying this defect by evaluating the expression of COX-2, a known stimulator of chondrocyte differentiation and maturation, in the growth plates of HexB–/– and wild-type mice. COX-2 expression was elevated in the cranial base synchondroses of HexB–/– mice (Fig. 2). In addition, the stress-activated p38 MAK, a known stimulator of COX-2, was also induced in growth plate chondrocytes (Fig. 2). Neonatal FIV(Hex) therapy resulted in the amelioration of this COX-2 induction in HexB–/– mice, suggesting a possible link to the genetic defect, COX-2 expression, and cranial base development (Fig. 4). COX-2 is rate-limiting in the production of prostanoids and prostaglandin PGE2 in particular, the effects of which are mediated by PGE2 (EP) receptors. We evaluated the effects of the COX2-PG pathway activation in chondrocyte maturation in vitro by using the C2C12 cell line (Fig. 4). Administration of PGE2 to differentiating C2C12 cells under the stimulus of BMP-2, an established cell culture system for the study of chondrocyte differentiation and maturation in vitro, resulted in acceleration of their conversion to an osteoblastic phenotype (number of cells converted in a defined period of time), suggesting that activation of the COX-PG pathway in HexB–/– chondrocytes may in fact induce the acceleration of chondrocyte maturation (Fig. 4).
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Figure 4. COX-2 activation is implicated in abnormal chondrocyte maturation secondary to β-hexosaminidase deficiency.GM2 ganglioside, the pathognomonic by-product of β-hexosaminidase deficiency, is selectively found in the proliferative and hypertrophic zones of HexB–/– cranial base synchondroses, as detected by immunohistochemistry with a monoclonal antibody. (A) Wild-type, (B) HexB–/–, and (C) FIV(HEX)-treated HexB–/– mice. Moreover, COX-2 expression correlated with GM2 storage in (D) wild-type, (E) HexB–/– mutant, and (F) FIV(HEX)- treated mice. To test whether chondrocyte maturation and differentiation are affected by the induction of the cyclo-oxygenase-prostaglandin pathway, we used the C2C12 cell line, an in vitro model of chondrocyte differentiation. To this end, the conversion of immature C2C12 cells to an osteoblastic phenotype was evaluated by assessment of the alkaline phosphatase expression in situ (black stain). (G) Untreated control cells showed no signs of conversion over a four-day period. Conversely, (H) treatment with BMP-2 (300 ng/mL) over 4 days induced the expression of alkaline phosphatase (black stain) in 10% of the cells in culture, suggesting a shift in their differentiation toward osteoblastic cells. Conversely, (I) treatment of C2C12 cells with BMP-2 plus PGE2 (10–8 M) over the same time period increased the number of cells expressing alkaline phosphatase by approximately five-fold, demonstrating the ability of PGE2 to increase the differentiation rate of C2C12 to osteoblastic cells (number of cells converted in a defined period of time). Representative images are shown here. *p < 0.05. Bar = 100 µm.
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DISCUSSION
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Our studies illustrate that impairment of chondrocyte maturation in the cranial base synchondroses of Sandhoff mice impairs craniofacial growth and development. We also expanded our analysis to the long bones’ growth plates, since they also develop via endochondral bone formation. Analysis of our data, collectively, suggests that the cranial base synchondroses of the HexB–/– mouse suffer uniquely, among the various growth plates, from a developmental aberration involving the type 2 collagen expressing proliferative chondrocytes. The phenotypic differences between the cranial base synchondroses and the long bone growth plates in the Sandhoff mouse model can be explained by the proximity of the cranial base to the inflamed brain. To this end, it is possible that brain-derived inflammatory factors, such as interleukin-1, may dissipate outside the brain and affect the development of proximal structures in a paracrine fashion. In contrast, the long bone growth plates are physically distanced from the brain, and thus are not affected by the brain inflammation. Since the observed skeletal anomalies could be rescued following systemic neonatal restitution of β-hexosaminidase by gene therapy, we concluded that perinatal chondrocyte differentiation and maturation at the cranial base synchondroses are paramount for normal craniofacial development. This conclusion is further supported by a study where neonatal transfer of human β-glucoronidase to Sly disease mice by an adenoviral vector offered short-term amelioration of craniofacial dysplasia (Kanaji et al., 2003).
Several growth factors regulate chondrocyte differentiation and maturation. PTHrP acts both as an inducer of chondrogenic commitment (de Crombrugghe et al., 2000) and as an inhibitor of chondrocyte hypertrophic progression (Ionescu et al., 2001). Another osteogenesis-associated gene found up-regulated in the HexB–/– chondrocytes was COX-2. Several studies have suggested an important role for the COX-2 pathway in chondrogenesis and bone development (Wong et al., 1977; Mankin and Zaleske, 1998). Systemic injection of PGE2 results in thinner growth plates with smaller hypertrophic chondrocytes and reduced limb growth (Ueno et al., 1985; Furuta and Jee, 1986). In addition, prostaglandins stimulate growth plate chondrocyte proliferation and sulfate incorporation (O’Keefe et al., 1992), while inhibiting growth plate maturation (Li et al., 2004; Zhang et al., 2004). Hence, it is possible that the observed COX-2 induction in Sandhoff chondrocytes may play an important role in the development of skeletal dysplasia in these mice. In conclusion, timely restitution of a genetic deficiency or, alternatively, the restoration of PTHrP or cyclo-oxygenase activity by the administration of PTH and/or non-steroidal anti-inflammatory drugs or COX-2 selective inhibitors to affected individuals may prove beneficial in the management of midface retrusion.
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ACKNOWLEDGMENTS
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This work was supported by the University of Rochester Eastman Dental Center and by grants NS48339 and DE14700, awarded to SK from the National Institutes of Health.
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FOOTNOTES
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A supplemental appendix to this article is published electronically only at http://www.dentalresearch.org.
Received for publication February 10, 2006.
Revision received May 4, 2007.
Accepted for publication May 31, 2007.
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Journal of Dental Research, Vol. 86, No. 10,
956-961 (2007)
DOI: 10.1177/154405910708601008
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ABSTRACT
INTRODUCTION