Paul C. Dechow

Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ

The endocrine hormone fibroblast growth factor 21 (FGF21) is a powerful modulator of glucose and lipid metabolism and a promising drug for type 2 diabetes. Here we identify FGF21 as a potent regulator of skeletal homeostasis. Both genetic and pharmacologic FGF21 gain of function lead to a striking decrease in bone mass. In contrast, FGF21 loss of function leads to a reciprocal high-bone-mass phenotype. Mechanistically, FGF21 inhibits osteoblastogenesis and stimulates adipogenesis from bone marrow mesenchymal stem cells by potentiating the activity of peroxisome proliferator-activated receptor γ (PPAR-γ). Consequently, FGF21 deletion prevents the deleterious bone loss side effect of the PPAR-γ agonist rosiglitazone. Therefore, FGF21 is a critical rheostat for bone turnover and a key integrator of bone and energy metabolism. These results reveal that skeletal fragility may be an undesirable consequence of chronic FGF21 administration.

Normal masticatory performance in young adults and children

Previous studies have paid little attention to either the development or sexual dimorphism of masticatory performance. The aim of this study was to measure and compare the masticatory performance of adults and children. Forty-seven healthy and normal individuals (15 adult men, 15 adult women, 15 young girls and 2 young boys) were selected, based on their occlusion, temporomandibular joint function, skeletal classification, and the state of their dentition. Masticatory performance was evaluated by the individuals ability to break down a standardized bolus. Cuttersil impression material was chewed for 20 strokes, spat out, dried, and passed through a series of seven sieves. The Rosin-Rammler equation was used to calculate the median particle size and broadness of particle distribution. Measurements of dentitional surface area, contact area, bite force, mandibular morphology, and body size were also taken as covariates. The results showed significant differences in masticatory performance among the three larger groups; men performed best, followed by women then girls. Multiple regression analyses showed that body size was the most important variable associated with differences in masticatory performance. Adjusting for weight eliminated the group differences. Body size, together with the occlusal contact area of the posterior teeth and the bite force, explained 60-72 percent of the variation in performance. Contact area, posterior ramus height, and bite force explained differences between men and women, but differences between adults and children remained.

Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy

Chronic kidney disease–mineral bone disorder (CKD‐MBD) is defined by abnormalities in mineral and hormone metabolism, bone histomorphometric changes, and/or the presence of soft‐tissue calcification. Emerging evidence suggests that features of CKD‐MBD may occur early in disease progression and are associated with changes in osteocyte function. To identify early changes in bone, we utilized the jck mouse, a genetic model of polycystic kidney disease that exhibits progressive renal disease. At 6 weeks of age, jck mice have normal renal function and no evidence of bone disease but exhibit continual decline in renal function and death by 20 weeks of age, when approximately 40% to 60% of them have vascular calcification. Temporal changes in serum parameters were identified in jck relative to wild‐type mice from 6 through 18 weeks of age and were subsequently shown to largely mirror serum changes commonly associated with clinical CKD‐MBD. Bone histomorphometry revealed progressive changes associated with increased osteoclast activity and elevated bone formation relative to wild‐type mice. To capture the early molecular and cellular events in the progression of CKD‐MBD we examined cell‐specific pathways associated with bone remodeling at the protein and/or gene expression level. Importantly, a steady increase in the number of cells expressing phosphor‐Ser33/37‐β‐catenin was observed both in mouse and human bones. Overall repression of Wnt/β‐catenin signaling within osteocytes occurred in conjunction with increased expression of Wnt antagonists (SOST and sFRP4) and genes associated with osteoclast activity, including receptor activator of NF‐κB ligand (RANKL). The resulting increase in the RANKL/osteoprotegerin (OPG) ratio correlated with increased osteoclast activity. In late‐stage disease, an apparent repression of genes associated with osteoblast function was observed. These data confirm that jck mice develop progressive biochemical changes in CKD‐MBD and suggest that repression of the Wnt/β‐catenin pathway is involved in the pathogenesis of renal osteodystrophy.

PGC1β Mediates PPARγ Activation of Osteoclastogenesis and Rosiglitazone-Induced Bone Loss

Long-term usage of rosiglitazone, a synthetic PPARgamma agonist, increases fracture rates among diabetic patients. PPARgamma suppresses osteoblastogenesis while activating osteoclastogenesis, suggesting that rosiglitazone decreases bone formation while sustaining or increasing bone resorption. Using mouse models with genetically altered PPARgamma, PGC1beta, or ERRalpha, here we show that PGC1beta is required for the resorption-enhancing effects of rosiglitazone. PPARgamma activation indirectly induces PGC1beta expression by downregulating beta-catenin and derepressing c-jun. PGC1beta, in turn, functions as a PPARgamma coactivator to stimulate osteoclast differentiation. Complementarily, PPARgamma also induces ERRalpha expression, which coordinates with PGC1beta to enhance mitochondrial biogenesis and osteoclast function. ERRalpha knockout mice exhibit osteoclast defects, revealing ERRalpha as an important regulator of osteoclastogenesis. Strikingly, PGC1beta deletion in osteoclasts confers complete resistance to rosiglitazone-induced bone loss. These findings identify PGC1beta as an essential mediator for the PPARgamma stimulation of osteoclastogenesis by targeting both PPARgamma itself and ERRalpha, thus activating two distinct transcriptional programs.

Development of the nose and soft tissue profile

Cephalometric radiographs from a sample of 64 untreated persons (32 Class I and 32 Class II) were evaluated to determine the amount, direction and timing of facial soft tissue development. Twenty-five parameters were evaluated in the mixed dentition (7 to 9 years), the early permanent dentition (11 to 13 years), and early adulthood (16 to 18 years). Results showed that anteroposterior growth and subsequent increased anterior projection of the nose continued in both males and females after skeletal growth had subsided. However, females had concluded a large proportion of their soft tissue development by age 12 while in males continued growth was noted until age 17 resulting in their having greater soft tissue dimensions for many of the parameters evaluated. During the developmental period, the angular shapes and positional relationships of the nose, lips and chin remained relatively constant for both sexes and was relatively independent of the underlying hard tissues. Treatment planning implications may be drawn from the amounts and timing of the soft tissue development found in this study.

Elastic properties and masticatory bone stress in the macaque mandible.

One important limitation of mechanical analyses with strain gages is the difficulty in directly estimating patterns of stress or loading in skeletal elements from strain measurements. Because of the inherent anisotropy in cortical bone, orientation of principal strains and stresses do not necessarily coincide, and it has been demonstrated theoretically that such differences may be as great as 45 degrees (Cowin and Hart, 1990). Likewise, relative proportions of stress and strain magnitudes may differ. This investigation measured the elastic properties of a region of cortical bone on both the buccal and lingual surfaces of the lower border of the macaque mandible. The elastic property data was then combined with macaque mandibular strain data from published and a new in vivo strain gage experiment to determine directions and magnitudes of maximum and minimum principal stresses. The goal was to compare the stresses and strains and assess the differences in orientation and relative magnitude between them. The main question was whether these differences might lead to different interpretations of mandibular function. Elastic and shear moduli, and Poissons ratios were measured using an ultrasonic technique from buccal and lingual cortical surfaces in 12 macaque mandibles. Mandibular strain gage data were taken from a published set of experiments (Hylander, 1979), and from a new experiment in which rosette strain gauges were fixed to the buccal and lingual cortices of the mandibular corpus of an adult female Macaca fascicularis, after which bone strain was recorded during mastication. Averaged elastic properties were combined with strain data to calculate an estimate of stresses in the mandibular corpus. The elastic properties were similar to those of the human mandibular cortex. Near its lower border, the macaque mandible was most stiff in a longitudinal direction, less stiff in an inferosuperior direction, and least stiff in a direction normal to the bones surface. The lingual aspect of the mandible was slightly stiffer than the buccal aspect. Magnitudes of stresses calculated from average strains ranged from a compressive stress of -16.00 GPa to a tensile stress of 8.84 GPa. The orientation of the principal stresses depended on whether the strain gage site was on the working or balancing side. On the balancing side of the mandibles, maximum principal stresses were oriented nearly perpendicular to the lower border of the mandible. On the working side of the mandibles, the orientation of the maximum principal stresses was more variable than on the balancing side, indicating a larger range of possible mechanisms of loading. Near the lower border of the mandible, differences between the orientation of stresses and strains were 12 degrees or less. Compared to ratios between maximum and minimum strains, ratios between maximum and minimum stresses were more divergent from a ratio of 1.0. Results did not provide any major reinterpretations of mandibular function in macaques, but rather confirmed and extended existing work. The differences between stresses and strains on the balancing side of the mandible generally supported the view that during the power stroke the mandible was bent and slightly twisted both during mastication and transducer biting. The calculated stresses served to de-emphasize the relative importance of torsion. On the working side, the greater range of variability in the stress analysis compared to the strain analysis suggested that a more detailed examination of loadings and stress patterns in each individual experiment would be useful to interpret the results. Torsion was evident on the working side; but in a number of experiments, further information was needed to interpret other superimposed regional loading patterns, which may have included parasagittal bending and reverse parasagittal bending.

Edentulation Alters Material Properties of Cortical Bone in the Human Mandible

Ridge resorption following edentulation has been documented clinically, but the effects of tooth loss on the material properties of mandibular cortical bone have received little study. Material properties and their structural basis are essential for our understanding of bone quality in the edentulous mandible and are of interest as a tissue-level model for functional adaptation. This study’s aim was to determine material property variability in the edentulous mandible, and to compare it with data from a previous study of dentate mandibles. Forty-four cortical samples were removed from each of 10 adult fresh edentulous mandibles. Cortical thickness and density were measured. Material properties were calculated from ultrasonic velocities. Mandibular cortical bone in the edentulous mandibles differed from that of dentate mandibles in cortical thickness, elastic and shear moduli, anisotropy, and orientation of the axis of maximum stiffness. These results suggest that cortical microstructural changes accompany ridge resorption following edentulation.

In vivo bone strain and finite-element modeling of the craniofacial haft in catarrhine primates.

Hypotheses regarding patterns of stress, strain and deformation in the craniofacial skeleton are central to adaptive explanations for the evolution of primate craniofacial form. The complexity of craniofacial skeletal morphology makes it difficult to evaluate these hypotheses with in vivo bone strain data. In this paper, new in vivo bone strain data from the intraorbital surfaces of the supraorbital torus, postorbital bar and postorbital septum, the anterior surface of the postorbital bar, and the anterior root of the zygoma are combined with published data from the supraorbital region and zygomatic arch to evaluate the validity of a finite‐element model (FEM) of a macaque cranium during mastication. The behavior of this model is then used to test hypotheses regarding the overall deformation regime in the craniofacial haft of macaques. This FEM constitutes a hypothesis regarding deformation of the facial skeleton during mastication. A simplified verbal description of the deformation regime in the macaque FEM is as follows. Inferior bending and twisting of the zygomatic arches about a rostrocaudal axis exerts inferolaterally directed tensile forces on the lateral orbital wall, bending the wall and the supraorbital torus in frontal planes and bending and shearing the infraorbital region and anterior zygoma root in frontal planes. Similar deformation regimes also characterize the crania of Homo and Gorilla under in vitro loading conditions and may be shared among extant catarrhines. Relatively high strain magnitudes in the anterior root of the zygoma suggest that the morphology of this region may be important for resisting forces generated during feeding.

In vitro strain measurements in the condylar process of the human mandible

Although there have been a number of experimental studies of temporomandibular joint loading, the precise relation between condylar load and condylar strain is incompletely understood. This in vitro study determined the magnitudes and directions of the principal components of strain on the four surfaces of the condylar process of human cadaver mandibles during loading with selected simulated muscle forces, with simultaneous measurement of occlusal and joint forces. Rosette strain gauges were placed on each of the four surfaces and the mandibles were loaded by a load cell to simulate the action of the masseter and medial pterygoid muscles. Force and strain values were measured at five different bite positions and nine different positions of the resultant muscle force. Forces and strain values were highest when the resultant muscle force was closest to the joint and the bite position was furthest from the joint. The ratios of bite force to joint force and the ratios of forces between the two joints conformed to theoretical predictions of many previous models, with the balancing-side joint being loaded more heavily than the working-side joint. At all gauge positions the maximum principal strain was tensile, the minimum principal strain was compressive, and the absolute strain values were correlated with the magnitude of the force on the condyle. However, under the chosen loading regimen, the ratio of compressive to tensile strain differed among the four surfaces. The highest levels of tensile strain occurred on the anterior and lateral surfaces and the highest compressive strain occurred on the posterior surface.(ABSTRACT TRUNCATED AT 250 WORDS)

Material properties of the inner and outer cortical tables of the human parietal bone

Even though the cranial vault functions as protection for the brain and as a support structure for facial and masticatory functions, little is known about its mechanical properties or their variations. The cranial vault bone is interesting because of its maintenance in spite of low functional strains, and because calvarial bone cells are often used in cell culture studies. We measured thickness, density, and ash weight, and ultrasonically determined elastic properties throughout the cortices of 10 human parietal bones. The results are unique for studies of the cranial vault because: 1) measurements focused specifically on the cortical components, 2) the orientations of the axes of maximum stiffness were determined before measurement of elastic properties, and 3) two related measurements (bone density and percent ash weight) were compared. Results showed that the periosteal cortical plate (outer table) and the endosteal cortical plate (inner table) had significant differences in material properties. The outer table was on average thicker, denser, and stiffer than the inner table, which had a higher ash weight percentage. Within each table there were significant differences in thicknesses, ash weight percentages, and E2/E3 anisotropies among sites. Few sites on either table had significant orientations of the axes of maximum stiffness. Despite this apparent randomness in orientation, almost all sites exhibited anisotropies equivalent to other parts of the skeleton. Anat Rec 268:7–15, 2002.