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Discoidin Domain Receptor 1 (DDR1) is a receptor tyrosine kinase that binds to and is activated by collagen(s), including collagen type I. Ddr1 deletion in osteoblasts and chondrocytes has previously demonstrated the importance of this receptor in bone development. In this study, we examined the effect of DDR1 ablation on bone architecture and mechanics as a function of aging. Femurs were collected from female global Ddr1 knockout (KO) and wild-type (WT) mice at 2, 6, and 12 mo of age and analyzed by high-resolution micro-computed tomography (μCT), mechanical testing, and histology. Primary monocytes were collected for in vitro osteoclastogenesis assays. Our studies on younger (2 mo) mice revealed no significant differences between the two genotypes and the microarchitectural and mechanical features had a similar trend as those reported earlier for osteoblast or chondrocyte specific Ddr1 knockdown. At an advanced age (12 mo), significant differences were noted across the two genotypes. μCT analysis showed a decrease in medullary cavity area as well as increased trabeculation in cortical and trabecular bone in the Ddr1 KO vs. WT mice. In addition, Ddr1 KO mouse bones exhibited reduced mechanical properties (lower peak load, yield load, and energy to yield) at 12 mo. Histological analysis revealed reduced osteoclast count in Ddr1 KO femurs at 12 mo with no significant difference in osteocyte count between the genotypes. In vitro, osteoclastogenesis was impaired in Ddr1 KO bone marrow derived cells. These results suggest that DDR1 deficiency adversely impacts osteoclast differentiation and bone remodeling in an age-dependent manner. 

The sphenoid bone articulates with multiple basicranial, facial, and calvarial bones, and in humans its synchondroses are known to contribute to elongation of the skull base and possibly to cranial base angulation. Its early development (embryological, early fetal) has frequently been studied in a comparative context. However, the perinatal events in morphogenesis of the sphenoid have been explored in very few primates. Using a cross-sectional age sample of non-human primates (n=39; 22 platyrrhines; 17 strepsirrhines), we used microcomputed tomographic (µCT) and histological methods to track age changes in the sphenoid bone. In the midline, the sphenoid expands its dimensions at three growth centers, including the sphenooccipital, intrasphenoidal (ISS) and presphenoseptal (PSept) synchondroses. Bilaterally, the alisphenoid is enlarged via appositional bone growth that radiates outward from cartilaginous parts of the alisphenoid during midfetal stages. The alisphenoid remains connected to the basitrabecular process of the basisphenoid via the alibasisphenoidal synchondrosis (ABS). Reactivity to proliferating cell-nuclear antigen is observed in all synchondroses, indicating active growth perinatally. Between mid-fetal and birth ages in Saguinus geoffroyi , all synchondroses decrease in the breadth of proliferating columns of chondrocytes. In most primates, the ABS is greatly diminished by birth, and is likely the earliest to fuse, although at least some cartilage may remain by at least one-month of age. Unlike humans, no non-human primate in our sample exhibits perinatal fusion of ISS. A dichotomy among primates is the orientation of the ABS, which is more rostrally directed in platyrrhines. Based on fetal Saguinus geoffroyi specimens, the ABS was initially oriented within a horizontal plane, and redirects inferiorly during late fetal and perinatal stages. These changes occur in tandem with forward orientation of the orbits in platyrrhines, combined with downward growth of the midface. Thus, we postulate that active growth centers direct the orientation of the midface and orbit before birth. 

Abstract ObjectivesThe aim of the present study is to broaden our knowledge of the ontogeny of cranial base cartilaginous joints in primates. Materials and MethodsA cross‐sectional age sample of 66 specimens from four platyrrhine and three strepsirrhine genera were studied using microcomputed tomography, histology, and immunohistochemistry. Specimens were segmented, reconstructed, and measured using Amira software. Ontogenetic scaling of palatal, presphenoid, and basisphenoid length relative to cranial length was examined using standardized major axis regression. After histological sectioning, selected specimens were examined using immunohistochemistry of antibodies to proliferating cell nuclear antigen. ResultsOur results support the hypothesis that the presphenoid in platyrrhines grows more rapidly compared with strepsirrhines, but this study establishes that most or all of this growth discrepancy occurs prenatally, and mostly at the presphenoseptal synchondrosis (PSept). All species have prolonged patency (here meaning absence of any bony bridging across the synchondrosis) of the intrasphenoidal and spheno‐occipital synchondroses (ISS). However, immunohistochemical results suggest growth is only rapid throughout infancy, and mitotic activity is slowing during juvenile ages. The same is indicated for the PSept. DiscussionThese results demonstrate that platyrrhines and strepsirrhines do not follow the pattern of early fusion of ISS seen in humans. In addition, these primates have a more prolonged patency and growth at PSept compared with humans. Finally, results reveal that in bushbabies and tamarins, as in humans, synchondroses remain cartilaginous for a prolonged period after chondrocyte proliferation has slowed or ceased. In light of these results, it is time to reassess related processes, such as differences in timing of brain expansion.