Biomedical subjects

Pamela Gehron Robey

Publications and source records attributed to Pamela Gehron Robey.

At least 19 recordsLinked to original sources

PubMed2006

In vivo bone formation by human bone marrow stromal cells: reconstruction of the mouse calvarium and mandible.

Bone marrow stromal cells (BMSCs) contain a subset of multipotent cells with the potential to repair hard-tissue defects. Mouse BMSCs, combined with a collagen carrier, can close critical-sized homologous mouse calvarial defects, but this new bone has a poor union with the adjacent calvarium. When human BMSCs are transplanted for the purpose of engineering new bone, best results can be achieved if the cells are combined with hydroxyapatite/tricalcium phosphate (HA/TCP) particles. Here, we demonstrate that transplantation of cultured human BMSCs in conjunction with HA/TCP particles can be used successfully to close mouse craniofacial bone defects and that removal of the periosteum from the calvarium significantly enhances union with the transplant. Transplants were followed for up to 96 weeks and were found to change in morphology but not bone content after 8 weeks; this constitutes the first description of human BMSCs placed long-term to heal bone defects. New bone formation continued to occur in the oldest transplants, confirmed by tetracycline labeling. Additionally, the elastic modulus of this engineered bone resembled that of the normal mouse calvarium, and our use of atomic force microscopy (AFM)-based nanoindentation offered us the first opportunity to compare these small transplants against equally minute mouse bones. Our results provide insights into the long-term behavior of newly engineered orthotopic bone from human cells and have powerful implications for therapeutic human BMSC transplantation.

Animals↗

PubMed2006

In vitro chromosome aberration tests using human dental pulp cells to detect the carcinogenic potential of chemical agents.

To examine if human dental pulp cells are useful for assessing the carcinogenic potential of chemical agents, we cultured human dental pulp cells from adults and studied the ability of chemical agents known to be carcinogenic to induce chromosome aberrations in these cells. We confirmed that human dental pulp cells in primary or secondary cultures had the capability of accumulating calcium in vitro as detected by Alizarin red staining and generating dentin-like tissue in immunocompromised mice. These phenotypes were maintained even in cells at seven passages. Next, we examined if chromosome aberrations were induced by exposure of human dental pulp cells (designated here as D824 cells) at seven to nine passages to chemical agents with carcinogenic activity. Statistically significant increases in the frequencies of chromosome aberrations were induced in D824 cells treated with a direct-acting carcinogen, mitomycin C, for 3 h. Chromosome aberrations were also induced at statistically significant levels in D824 cells treated with an indirect-acting carcinogen, cyclophosphamide, for 2 h in the presence of exogenous metabolic activation with rat liver postmitochondrial supernatant. Cyclophosphamide failed to induce chromosome aberrations in the absence of exogenous metabolic activation. Although the reliability of chromosome aberration tests using human dental pulp cells remains to be validated by studying the ability of various other chemical agents with or without carcinogenic activity to induce chromosome aberrations, this chromosome aberration test system may be useful for carcinogenic risk assessment in the target cells.

Adolescent↗

PubMed2006

Postnatal skeletal stem cells.

Postnatal skeletal stem cells are a subpopulation of the bone marrow stromal cell network. To date, the most straightforward way of assessing the activity of skeletal stem cells within the bone marrow stromal cell (BMSC) population is via analysis of the rapidly adherent, colony-forming unit-fibroblast (CFU-F), and their progeny, BMSCs. Several in vitro methods are employed to determine the differentiation capacity of BMSCs, using osteogenic and adipogenic "cocktails" and staining protocols, and pellet cell culture for chondrogenic differentiation. However, true differentiation potential is best determined by in vivo transplantation in either closed or open systems. By in vivo transplantation, approximately 10% of the clonal strains are able to form bone, stroma, and marrow adipocytes, and are true skeletal stem cells. Furthermore, when derived from patients or animal models with abnormalities in gene expression, they recapitulate the disease phenotype on in vivo transplantation. Although ex vivo expansion of BMSCs inevitably dilutes the skeletal stem cells, when used en masse, they are attractive candidates for reconstruction of segmental bone defects, and as targets for gene therapy.

Adult Stem Cells↗

PubMed2006

Monostotic fibrous dysplasia of the proximal femur and liposclerosing myxofibrous tumor: which one is which?

Clinical, histological, and genetic studies of two cases of isolated fibro-osseous lesions of the femur in adults show the overlap between monostotic fibrous dysplasia (MFD) of the proximal femur and the so-called liposclerosing myxofibrous tumor. The two cases highlight how the incomplete understanding of the natural history of MFD may result in diagnostic pitfalls or incorrect classification of individual lesions.

Adult↗

PubMed2006

Fibrous dysplasia as a stem cell disease.

At a time when significant attention is devoted worldwide to stem cells as a potential tool for curing incurable diseases, fibrous dysplasia of bone (FD) provides a paradigm for stem cell diseases. Consideration of the time and mechanism of the causative mutations and of nature of the pluripotent cells that mutate in early embryonic development indicates that, as a disease of the entire organism, FD can be seen as a disease of pluripotent embryonic cells. As a disease of bone as an organ, in turn, FD can be seen as a disease of postnatal skeletal stem cells, which give rise to dysfunctional osteoblasts. Recognizing FD as a stem cell disease provides a novel conceptual angle and a way to generate appropriate models of the disease, which will continue to provide further insight into its natural history and pathogenesis. In addition, skeletal stem cells may represent a tool for innovative treatments. These can be conceived as directed to alter the in vivo behavior of mutated stem cells, to replace mutated cells through local transplantation, or to correct the genetic defect in the stem cells themselves. In vitro and in vivo models are currently being generated that will permit exploration of these avenues in depth.

Bone and Bones↗

PubMed2006

The use of adult stem cells in rebuilding the human face.

BACKGROUND: Stem cells have been isolated from a variety of embryonic and postnatal (adult) tissues, including bone marrow. Bone marrow stromal cells (BMSCs), which are non-blood-forming cells in marrow, contain a subset of skeletal stem cells (SSCs) that are able to regenerate all types of skeletal tissue: bone, cartilage, blood-supportive stromal cells and marrow fat cells. METHODS: Bone marrow suspensions are placed into culture for analysis of their biological character and for expansion of their number. The resulting populations of cells are used in a variety of assays to establish the existence of an adult SSC, and the ability of BMSC populations to regenerate hard tissues in the craniofacial region, in conjunction with appropriate scaffolds. RESULTS: Single-cell analysis established the existence of a true adult SSC in bone marrow. Populations of ex vivo expanded BMSCs (a subset of which are SSCs) are able to regenerate a bone/marrow organ. In conjunction with appropriate scaffolds, these cells can be used to regenerate bone in a variety of applications. CONCLUSIONS: BMSCs have the potential to re-create tissues of the craniofacial region to restore normal structure and function in reconstructing the hard tissues of a face. Ex vivo expanded BMSCs with scaffolds have been used in a limited number of patients to date, but likely will be used more extensively in the near future.

Adult↗

PubMed2006

The correlation of specific orthopaedic features of polyostotic fibrous dysplasia with functional outcome scores in children.

BACKGROUND: Polyostotic fibrous dysplasia has a wide clinical spectrum, with substantial variation between patients in terms of orthopaedic manifestations, including the number of fractures, the degree of deformity of the limbs, and the presence of scoliosis. Data from bone scans, skeletal surveys, and records were correlated with the Pediatric Outcomes Data Collection Instrument scales to examine whether any specific facet of orthopaedic involvement could be related to functional abilities. METHODS: All patients who were sixteen years of age or younger and who were part of an ongoing natural history study of polyostotic fibrous dysplasia (including McCune-Albright syndrome) were sent an age-appropriate Pediatric Outcomes Data Collection Instrument outcomes tool. The medical records and radiographs of the patients who returned forms were reviewed. Radiographic measurements of scoliosis, the femoral neck-shaft angle, and limb deformities were then performed. The extent of skeletal involvement with polyostotic fibrous dysplasia (disease burden) was assessed on bone scans with use of a validated tool. A chart review was performed to determine the fracture rate, the use of bisphosphonates, and the endocrine status. These measurements were correlated with the Pediatric Outcomes Data Collection Instrument scores. RESULTS: The outcomes tool was sent to twenty-seven patients and the completed instrument was returned by twenty patients, for a response rate of 74%. The parent-child form was filled out for twelve patients and the parent-adolescent form was filled out for eight patients. The mean standardized Pediatric Outcomes Data Collection Instrument scores for all twenty patients were lowest for sports (62; range, 14 to 100) and happiness (72; range, 25 to 100). Adolescents and parents disagreed with regard to sports (with adolescent scores being higher than parental scores) and pain (with parental scores being higher than adolescent scores). However, the overall global scores correlated well between the parents and the adolescents (r = 0.78, p = 0.03). The femoral neck-shaft angle correlated strongly with the Pediatric Outcomes Data Collection Instrument score for sports (r = 0.46, p = 0.03) but not for transfers. The bone scan scores for the lower extremity disease burden correlated with both the transfer scale (r = 0.76, p = 0.03) and the sports scale (r = 0.77, p = 0.02). Deformity of the limbs, the presence of scoliosis, the prevalence of endocrine dysfunction, and the number of fractures did not correlate with the Pediatric Outcomes Data Collection Instrument scores. CONCLUSIONS: In patients with polyostotic fibrous dysplasia, the loss of the normal femoral neck-shaft angle and the disease burden in the lower extremities appear to have the greatest effect on functional activity as measured with the Pediatric Outcomes Data Collection Instrument tool.

Adolescent↗

PubMed2006

Canine cranial reconstruction using autologous bone marrow stromal cells.

Limited-sized transplants of culture-expanded autologous or allogeneic bone marrow stromal cells (BMSCs) form cortico-cancellous bone in rodent models. Initiation of clinical studies using autologous BMSC transplantation requires effective bone formation among sizable transplants in a large animal model as well as noninvasive techniques for evaluating transplant success. Here, we obtained bone marrow from the femurs of six dogs and expanded BMSCs in tissue culture. Autologous BMSC-hydroxyapatite/tricalcium phosphate (HA/TCP) transplants were introduced into critical-sized calvarial defects and contralateral control skull defects received HA/TCP vehicle alone. At intervals ranging from 2 to 20 months, transplants were biopsied or harvested for histological and mechanical analysis. Noninvasive studies, including quantitative computed tomography scans and ultrasound, were simultaneously obtained. In all animals, BMSC-containing transplants formed significantly more bone than their control counterparts. BMSC-associated bone possessed mechanical properties similar to the adjacent normal bone, confirmed by both ultrasound and ex vivo analysis. Evaluation by quantitative computed tomography confirmed that the extent of bone formation demonstrated by histology could be discerned through noninvasive means. These results show that autologous cultured BMSC transplantation is a feasible therapy in clinical-sized bone defects and that such transplants can be assessed noninvasively, suggesting that this technique has potential for use in patients with certain bone defects.

Animals↗

PubMed2005

Physical function is impaired but quality of life preserved in patients with fibrous dysplasia of bone.

Fibrous dysplasia of bone (FD) is a congenital, non-heritable skeletal disorder that is associated with multiple skeletal complications, including repeated fractures, limb length discrepancy, and bone pain. The disease-specific impact of FD on quality of life outcomes is unknown. We sought to understand the impact of the scope and extent of the skeletal disease on quality of life in adults and children with FD. The health-related quality of life was quantified in a population of adults (n = 56) and children (n = 22) with FD using validated health assessment questionnaires, the Medical Outcomes Study 36 Item Short-Form Health Survey, volume 2 (SF36) (adults) and the Child Health Questionnaire Parent Form 50 (CHQ-PF50) (children). Clinical demographic data and skeletal disease burden scores (SDBS, amount of skeleton involved with FD) were measured, and correlations with health-related quality of life were sought. The SF36 and CHQ-PF50 revealed lower Physical Function Summary scores in FD patients compared to the U.S. population norms (adult 41 vs. 50, Z score < -5.0, pediatric 39 vs. 50, Z score < -5.0). However, the SF36 and CHQ-PF50 Mental/Psychological summary scores were not different from those of U.S. population norms (adult 50 vs. 50, Z score = 0, pediatric 48 vs. 50 Z score = -0.9). The score on the Physical Function Domain of both tools was strongly negatively associated with the SDBS (adult Spearman rho = -0.43, P = 0.009, pediatric Spearman rho = -0.72, P = 0.005). The groups of adult and pediatric patients with SDBS > 30 had decreased Physical Function Domain scores when compared to those with scores < 30 (adult 35 vs. 45, P = 0.002, pediatric 57 vs. 78, P = 0.04, respectively). One of the largest effects was seen in the parents of children with FD, who had significantly lower Parental Emotional scores than those of the parents of healthy norms (54 vs. 88, Z score < -5.0), suggesting a high degree of emotional morbidity in the parents of children with FD. Despite measurable functional limitations in adults and children, and significant parental emotional impairment, patients with FD achieve a high level of social and emotional function. These data are important for prognosis and parental reassurance.

Activities of Daily Living↗

PubMed2004

The interplay of osteogenesis and hematopoiesis: expression of a constitutively active PTH/PTHrP receptor in osteogenic cells perturbs the establishment of hematopoiesis in bone and of skeletal stem cells in the bone marrow.

The ontogeny of bone marrow and its stromal compartment, which is generated from skeletal stem/progenitor cells, was investigated in vivo and ex vivo in mice expressing constitutively active parathyroid hormone/parathyroid hormone-related peptide receptor (PTH/PTHrP; caPPR) under the control of the 2.3-kb bone-specific mouse Col1A1 promoter/enhancer. The transgene promoted increased bone formation within prospective marrow space, but delayed the transition from bone to bone marrow during growth, the formation of marrow cavities, and the appearance of stromal cell types such as marrow adipocytes and cells supporting hematopoiesis. This phenotype resolved spontaneously over time, leading to the establishment of marrow containing a greatly reduced number of clonogenic stromal cells. Proliferative osteoprogenitors, but not multipotent skeletal stem cells (mesenchymal stem cells), capable of generating a complete heterotopic bone organ upon in vivo transplantation were assayable in the bone marrow of caPPR mice. Thus, PTH/PTHrP signaling is a major regulator of the ontogeny of the bone marrow and its stromal tissue, and of the skeletal stem cell compartment.

Animals↗

PubMed2004

An instrument to measure skeletal burden and predict functional outcome in fibrous dysplasia of bone.

UNLABELLED: An instrument to measure skeletal burden in fibrous dysplasia was developed. Biological and clinical relevance was shown by correlating skeletal burden scores with bone markers, quality of life, and ambulatory status. Childhood scores predict adult ambulatory status, and scores were unaffected when bone markers decreased with bisphosphonate treatment or aging. INTRODUCTION: Fibrous dysplasia (FD) is a skeletal disease with a broad clinical expression. There is no objective method to assess the extent of skeletal involvement or predict outcome. We developed an instrument to measure skeletal burden that correlates with physical function, health-related quality of life (HRQL), and ambulatory status. MATERIALS AND METHODS: Seventy-nine patients with FD underwent bone scintigraphy. The skeletal burden score was derived from a weighted score based on the regional measurement using bone scintigraphy to estimate the amount of FD in anatomical segments. Six readers scored 20 scans twice to determine the inter- and intrareader agreement. To assess biological significance, scores were correlated with bone markers. To assess functional outcome, scores on the SF-36 (adults) or CHQ-PF50 (children) were correlated with skeletal burden scores. In a group of patients who had bone scans as children and adults (n = 6), the ability to predict ambulatory status was tested. Skeletal burden scores were assessed in patients before and after treatment with pamidronate (n = 5). RESULTS: The inter- and intrareader agreement of burden scores were r = 0.96, and 0.98, respectively (p < 0.001 for both). The scores correlated with markers of bone metabolism and HRQL (Spearman rho, 0.54-0.67 p < 0.001 and -0.43, p = 0.001, respectively). The mean score of patients who ambulated unassisted was significantly lower than those requiring assistance (p < 0.001 unassisted versus crutch and/or wheelchair). In unassisted ambulators, younger patients had higher scores, suggesting high childhood scores may predict adulthood impairment. In six patients with childhood and adulthood scans, childhood scores >30 predicted assisted ambulation in adulthood. There was a negative correlation between bone markers and age (Spearman rho, -0.42 to -0.70; p < 0.001), but not age and skeletal burden score. Pamidronate treatment decreased serum alkaline phosphatase but had no effect on the skeletal burden score. CONCLUSIONS: This is a validated and reliable instrument for the measurement of skeletal burden of FD and is able to predict functional outcome.

Adolescent↗

PubMed2004

The small leucine-rich proteoglycan biglycan modulates BMP-4-induced osteoblast differentiation.

Biglycan (bgn) is a small leucine-rich proteoglycan enriched in extracellular matrices of skeletal tissues. Bgn-deficient mice develop age-related osteopenia with a phenotype that resembles osteoporosis and premature arthritis. In the present study, we have examined the differentiation of bgn-deficient osteoblasts from neonatal murine calvariae and found that the absence of bgn caused less BMP-4 binding, which reduced the sensitivity of osteoblasts to BMP-4 stimulation. The loss of sensitivity resulted in a reduction of Cbfa1 expression, which ultimately led to a defect in the differentiation of osteoblasts. However, the response of bgn-deficient osteoblasts to BMP-4 was completely rescued by reintroduction of biglycan by viral transfection. We propose that biglycan modulates BMP-4-induced signaling to control osteoblast differentiation.

Animals↗

PubMed2004

Bone formation in transplants of human bone marrow stromal cells and hydroxyapatite-tricalcium phosphate: prediction with quantitative CT in mice.

PURPOSE: To determine whether quantitative computed tomography (CT) can be used to estimate the extent of new bone formation in hydroxyapatite-tricalcium phosphate (HA-TCP)-based transplants. MATERIALS AND METHODS: Bone-forming transplants were generated by attaching cultured human bone marrow stromal cells to aliquots of HA-TCP particles and were placed in subcutaneous pockets in immunocompromised mice. After 8 weeks, the transplants were individually imaged; each scan included a phantom. Overall bone mineral density (BMD) of each transplant was obtained. Hematoxylin-eosin-stained sections of the same transplants were then examined histologically, which is the reference standard for assessing bone formation. The extent of bone in each transplant was scored on a semiquantitative scale ranging from 0 to 4 by three independent blinded observers; the bone score for each transplant was calculated by averaging the three observer scores. BMD was compared with the histologically determined bone score for each transplant. Statistical evaluations included (a) calculation of empiric receiver operating characteristic curves to determine optimum BMD thresholds and (b) determination of the relationship between BMD and bone score, including derivation of Pearson correlation coefficients. RESULTS: One hundred twenty transplants were evaluated. Average BMD of 600 mg/cm3 K2HPO4 or more was noted in transplants with appreciable bone formation (bone score > or = 3), while average BMD of less than 600 mg/cm3 K2HPO4 was seen in transplants with poor bone formation (bone score < 3) (P <.001). Among transplants with appreciable bone formation, the BMD was proportional to the extent of mineralized matrix present in the new bone. CONCLUSION: Use of quantitative CT offers a practical approach for the noninvasive determination of new bone formation in mineralizing bone marrow stromal cells and HA-TCP transplants.

Animals↗

PubMed2004

A crucial role of caspase-3 in osteogenic differentiation of bone marrow stromal stem cells.

Caspase-3 is a critical enzyme for apoptosis and cell survival. Here we report delayed ossification and decreased bone mineral density in caspase-3-deficient (Casp3(-/-) and Casp3(+/-)) mice due to an attenuated osteogenic differentiation of bone marrow stromal stem cells (BMSSCs). The mechanism involved in the impaired differentiation of BMSSCs is due, at least partially, to the overactivated TGF-beta/Smad2 signaling pathway and the upregulated expressions of p53 and p21 along with the downregulated expressions of Cdk2 and Cdc2, and ultimately increased replicative senescence. In addition, the overactivated TGF-beta/Smad2 signaling may result in the compromised Runx2/Cbfa1 expression in preosteoblasts. Furthermore, we demonstrate that caspase-3 inhibitor, a potential agent for clinical treatment of human diseases, caused accelerated bone loss in ovariectomized mice, which is also associated with the overactivated TGF-beta/Smad2 signaling in BMSSCs. This study demonstrates that caspase-3 is crucial for the differentiation of BMSSCs by influencing TGF-beta/Smad2 pathway and cell cycle progression.

Adult↗

PubMed2003

SHED: stem cells from human exfoliated deciduous teeth.

To isolate high-quality human postnatal stem cells from accessible resources is an important goal for stem-cell research. In this study we found that exfoliated human deciduous tooth contains multipotent stem cells [stem cells from human exfoliated deciduous teeth (SHED)]. SHED were identified to be a population of highly proliferative, clonogenic cells capable of differentiating into a variety of cell types including neural cells, adipocytes, and odontoblasts. After in vivo transplantation, SHED were found to be able to induce bone formation, generate dentin, and survive in mouse brain along with expression of neural markers. Here we show that a naturally exfoliated human organ contains a population of stem cells that are completely different from previously identified stem cells. SHED are not only derived from a very accessible tissue resource but are also capable of providing enough cells for potential clinical application. Thus, exfoliated teeth may be an unexpected unique resource for stem-cell therapies including autologous stem-cell transplantation and tissue engineering.

Animals↗

PubMed2003

Natural history and treatment of fibrous dysplasia of bone: a multicenter clinicopathologic study promoted by the European Pediatric Orthopaedic Society.

A multicenter study on fibrous dysplasia of bone (FD) was promoted by the European Pediatric Orthopaedic Society in 1999 in order to gain insight into the natural history of the disease and to evaluate current diagnostic and therapeutic approaches. We collected and reviewed clinical, radiographic, pathological, and molecular genetic data when possible, from a total of 64 cases diagnosed as either monostotic FD (MFD), polyostotic FD (PFD), or McCune-Albright syndrome (MAS), evaluated or treated in 11 participating centers. Results from the initial analysis of the series indicate five main points: (1) Significant diagnostic pitfalls affect the diagnosis of MFD and, to a lesser extent, PFD in orthopedic centers and allied radiology and pathology facilities, which may be circumvented by the adoption of stringent diagnostic criteria, and in some cases by the analysis of FD-associated GNAS1 mutations. (2) MFD carries a significant risk for fracture in the face of limited disease in the proximal femur, whereas its tendency to progress is restricted to a minority of cases, and long-term outcome is usually satisfactory, regardless of treatment, in non-progressive cases. (3) The profile of tibial disease, both in MFD and in PFD, is markedly different from that of femoral disease. (4) As expected, MAS patients have the most extensive disease and the most complicated course, regularly experience multiple fractures, and require adequate surgical treatment. It appears that conservative treatment of femoral fracture, or curettage and cancellous bone grafting, or fixation with screws and plates are not indicated for the treatment of femoral fractures in these patients and should all be discouraged. Internal fixation with intramedullary nails provides stabilization of extensively affected bones, and prevents further fractures and major deformities, and thus providing a better option both for acute and elective surgery in patients with extensive involvement of the femur or of other limb long bones. (5) Evaluation of patients with FD at orthopedic centers should include, but rarely does, a thorough evaluation of endocrine profile and phosphate metabolism, and proper pathological and radiographic assessment.

Adolescent↗

PubMed2003

FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting.

FGF-23, a novel member of the FGF family, is the product of the gene mutated in autosomal dominant hypophosphatemic rickets (ADHR). FGF-23 has been proposed as a circulating factor causing renal phosphate wasting not only in ADHR (as a result of inadequate degradation), but also in tumor-induced osteomalacia (as a result of excess synthesis by tumor cells). Renal phosphate wasting occurs in approximately 50% of patients with McCune-Albright syndrome (MAS) and fibrous dysplasia of bone (FD), which result from postzygotic mutations of the GNAS1 gene. We found that FGF-23 is produced by normal and FD osteoprogenitors and bone-forming cells in vivo and in vitro. In situ hybridization analysis of FGF-23 mRNA expression identified "fibrous" cells, osteogenic cells, and cells associated with microvascular walls as specific cellular sources of FGF-23 in FD. Serum levels of FGF-23 were increased in FD/MAS patients compared with normal age-matched controls and significantly higher in FD/MAS patients with renal phosphate wasting compared with those without, and correlated with disease burden bone turnover markers commonly used to assess disease activity. Production of FGF-23 by FD tissue may play an important role in the renal phosphate-wasting syndrome associated with FD/MAS.

Adolescent↗

PubMed2003

Osteomalacic and hyperparathyroid changes in fibrous dysplasia of bone: core biopsy studies and clinical correlations.

UNLABELLED: Deposition, mineralization, and resorption of FD bone compared with unaffected bone from FD patients was investigated in iliac crest biopsy specimens from 13 patients. Compared with unaffected bone, lesional FD bone seemed to be very sensitive to the effects of PTH and renal phosphate wasting, which respectively bring about hyperparathyroid or osteomalacic changes in the lesional bone. INTRODUCTION: Fibrous dysplasia is a genetic noninherited disease caused by activating mutations of the GNAS1 gene, resulting in the deposition of qualitatively abnormal bone and marrow. This study was designed to learn more about the local processes of bone deposition, mineralization, and resorption within lesional fibrous dysplasia (FD) bone compared with unaffected bone of FD patients. METHODS: Histology, histomorphometry, and quantitative back-scattered electron imaging (qBSE) analysis was conducted on affected and unaffected biopsy specimens from 13 patients and correlated to markers of bone metabolism. RESULTS AND CONCLUSIONS: There was a marked excess of unmineralized osteoid with a nonlamellar structure and a reduced mineral content in mineralized bone within FD lesions (p < 0.001). A negative correlation (p = 0.05) between osteoid thickness (O.Th) and renal tubular phosphate reabsorption (measured as TmP/GFR) was observed for lesional bone, but not for unaffected bone, in which no histological or histomorphometric evidence of osteomalacia was observed in patients with renal phosphate wasting. Histological and histomorphometric evidence of increased bone resorption was variable in lesional bone and correlated with serum levels of parathyroid hormone (PTH). Hyperparathyroidism-related histological changes were observed in fibrous dysplastic bone, but not in the unaffected bone, of patients with elevated serum PTH secondary to vitamin D deficiency. Our data indicate that, compared with unaffected bone, lesional FD bone is very sensitive to the effects of PTH and renal phosphate wasting, which, respectively, bring about hyperparathyroid or osteomalacic changes in the lesional bone. Osteomalacic and hyperparathyroid changes, which emanate from distinct metabolic derangements (which superimpose on the local effects of GNAS1 mutations in bone), influence, in turn, the severity and type of skeletal morbidity in FD.

Adolescent↗