Mesenchymal Stem Cells and Bovine Bone Mineral in Sinus Lift Procedures-An Experimental Study in Sheep

Introduction: New reconstructive and less invasive methods have been searched to optimize bone formation and osseointegration of dental implants in maxillary sinus augmentation. Purpose: The aim of the presented ovine split-mouth study was to compare bovine bone mineral (BBM) alone and in combination with mesenchymal stem cells (MSCs) regarding their potential in sinus augmentation. Material and Methods: Bilateral sinus floor augmentations were performed in six adult sheep. BBM and MSCs were placed into the test side and only BBM in the contra-lateral control side of each sheep. Animals were sacrificed after 8 and 16 weeks. Augmentation sites were analyzed by computed tomography, histology, and histomorphometry. Results: The initial volumes of both sides were similar and did not change significantly with time. A tight connection between the particles of BBM and the new bone was observed histologically. Bone formation was significantly (p = 0.027) faster by 49% in the test sides. Conclusion: The combination of BBM and MSCs accelerated new bone formation in this model of maxillary sinus augmentation. This could allow early placement of implants.

Mesenchymal stem cells and inorganic bovine bone mineral in sinus augmentation: comparison with augmentation by autologous bone in adult sheep

Our aim was to compare the osteogenic potential of mononuclear cells harvested from the iliac crest combined with bovine bone mineral (BBM) (experimental group) with that of autogenous cancellous bone alone (control group). We studied bilateral augmentations of the sinus floor in 6 adult sheep. BBM and mononuclear cells (MNC) were mixed and placed into one side and autogenous bone in the other side. Animals were killed after 8 and 16 weeks. Sites of augmentation were analysed radiographically and histologically. The mean (SD) augmentation volume was 3.0 (1.0) cm(3) and 2.7 (0.3) cm(3) after 8 and 16 weeks in the test group, and 2.8 (0.3) cm(3) (8 weeks) and 2.8 (1.2) cm(3) (16 weeks) in the control group, respectively. After 8 weeks, histomorphometric analysis showed 24 (3)% BBM, and 19 (11)% of newly formed bone in the test group. The control group had 20 (13%) of newly formed bone. Specimens after 16 weeks showed 29 (12%) of newly formed bone and 19 (3%) BBM in the test group. The amount of newly formed bone in the control group was 16 (6%). The results show that mononuclear cells, including mesenchymal stem cells, in combination with BBM as the biomaterial, have the potential to form bone. (C) 2009 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

A Clinical Study of 406 Sinus Augmentations With 100% Anorganic Bovine Bone

Background: The aim of the present study is to evaluate the use of anorganic bovine bone (ABB) associated with a collagen membrane (CM) for a sinus graft by means of clinical, histologic, and radiographic parameters in cases with bone availability <= 7 mm. A preliminary evaluation consisted of a clinical examination, computed tomography (CT), and a panoramic x-ray. Methods: Ninety-two patients requiring bilateral sinus grafts and 222 requiring unilateral procedures (total: 406 sinuses) participated in this study. A total of 1,025 implants were placed in the grafted sinuses. A total of 118 implants were placed simultaneously with the sinus graft (one stage), and 907 implants were placed in a subsequent surgery (two stages), 6 to 12 months after the graft was performed. In seven cases, a biopsy was harvested for histomorphometric analysis. Recall appointments were scheduled every 6 months, and panoramic and periapical x-rays were required every year for 3 years. Results: Among 1,025 implants, 19 were lost (survival rate: 98.1%). The difference in survival rates for implants placed in native bone: <= 3 mm (98.1%), >3 to <= 5 mm (98.6%), and >5 to <= 7 mm (97.0%) was not statistically significant (P = 0.3408). The survival rates for implants with rough and machined surfaces (98.6% and 97.0%, respectively) were not statistically significant (P = 0.0840). The histomorphometric analysis showed new bone formation (39.0% +/- 12%), marrow space (52.9% +/- 9.3%), and residual ABB (8% +/- 2.7%). Conclusion: Our results indicated that 1,025 implants placed in sinuses grafted exclusively with ABB combined with CM led to an excellent and predictable survival rate of 98.1%. J Periodontol 2009;80:1920-1927.

Ridge Preservation With Acellular Dermal Matrix and Anorganic Bone Matrix Cell-Binding Peptide P-15 After Tooth Extraction in Humans

Background: Preventing ridge collapse with the extraction of maxillary anterior teeth is vital to an esthetic restorative result. Several regenerative techniques are available and are used for socket preservation. The aim of this study is to analyze by clinical parameters the use of acellular dermal matrix (ADM) and anorganic bovine bone matrix (ABM) with synthetic cell-binding peptide P-15 to preserve alveolar bone after tooth extraction. Methods: Eighteen patients in need of extraction of maxillary anterior teeth were selected and randomly assigned to the test group (ADM plus ABM/P-15) or the control group (ADM only). Clinical measurements were recorded initially and at 6 months after ridge-preservation procedures. Results: In the clinical measurements (external vertical palatal measurement [EVPM], external vertical buccal measurement [EVBM], and alveolar horizontal measurement [AHM]) the statistical analysis showed no difference between test and control groups initially and at 6 months. The intragroup analysis, after 6 months, showed a statistically significant reduction in the measurements for both groups. In the comparison between the two groups, the differences in the test group were as follows: EVPM = 0.83 +/- 1.53 mm; EVBM = 1.20 +/- 2.02 mm; and AHM = 2.53 +/- 1.81 mm. The differences in the control group were as follows: EVPM = 0.87 +/- 1.13 mm; EVBM = 1.50 +/- 1.15 mm; and AHM = 3.40 +/- 1.39 mm. The differences in EVPM and EVBM were not statistically significant; however, in horizontal measurement (AHM), there was a statistically significant difference (P<0.05). Conclusion: The results of this study show that ADM used as membrane associated with ABM/P-15 can be used to reduce buccal-palatal dimensions compared to ADM alone for preservation of the alveolar ridge after extraction of anterior maxillary teeth. J Periodontol 2011;82:72-79.

Influence of rhBMP-2 on bone formation and osseointegration in different implant systems after sinus-floor elevation. An in vivo study on sheep

Background Several studies have reported certain bone morphogenic proteins (BMPs) to have positive effects on bone generation Although some investigators have studied the effects of human recombinant BMP (rhBMP-2) in sinus augmentation in sheep, none of these studies looked at the placement of implants at the time of sinus augmentation Furthermore, no literature could be found to report on the impact that different implant systems, as well as the positioning of the implants had on bone formation if rhBMP-2 was utilized in sinus-lift procedures Purpose The aim of this study was to compare sinus augmentation with rhBMP-2 on a poly-D, L-lactic-co-glycolic acid gelatine (PLPG) sponge with sinus augmentation with autologous pelvic cancellous bone in the maxillary sinus during the placement of different dental Implants Materials and methods Nine adult female sheep were submitted to bilateral sinus-floor elevation In one side (test group) the sinus lift was performed with rhBMP-2 on a PLPG-sponge, while the contralateral side served as the control by using cancellous bone from the iliac crest Three different implants (Branemark (R), 31 (R) and Straumann (R)) were inserted either simultaneously with the sinus augmentation or as a two staged procedure 6 weeks later The animals were sacrificed at 6 and 12 weeks for histological and histomorphometrical evaluations during which bone-to-implant contact (BIC) and bone density (BD) were evaluated Results BD and BIC were significantly higher at 12 weeks in the test group if the Implants were placed at the time of the sinus lift (p < 0 05) No difference was observed between the different implant systems or positions Conclusions The use of rhBMP-2 with PLPG-sponge increased BIC as well as BD in the augmented sinuses if compared to autologous bone Different implant systems and positions of the implants had no effect on BIC or BD (C) 2010 European Association for Cranio-Maxillo-Facial Surgery

In Vivo Comparison of Hard Tissue Regeneration with Human Mesenchymal Stem Cells Processed with Either the FICOLL Method or the BMAC Method

Objective: To compare new bone formation in maxillary sinus augmentation procedures using biomaterial associated with mesenchymal stem cells (MSCs) separated by two different isolation methods. Background: In regenerative medicine open cell concentration systems are only allowed for clinical application under good manufacturing practice conditions. Methods: Mononuclear cells, including MSCs, were concentrated with either the synthetic poylsaccharid (FICOLL) method (classic open system-control group, n = 6 sinus) or the bone marrow aspirate concentrate (BMAC) method (closed system-test group, n = 12 sinus) and transplanted in combination with biomaterial. A sample of the cells was characterized by their ability to differentiate. After 4.1 months (SD +/- 1.0) bone biopsies were obtained and analyzed. Results: The new bone formation in the BMAC group was 19.9% (90% confidence interval [CI], 10.9-29), and in the FICOLL group was 15.5% (90% CI, 8.6-22.4). The 4.4% difference was not significant (90% CI, -4.6-13.5; p = 0.39). MSCs could be differentiated into osteogenic, chondrogenic, and adipogenic lineages. Conclusion: MSCs harvested from bone marrow aspirate in combination with bovine bone matrix particles can form lamellar bone and provide a reliable base for dental implants. The closed BMAC system is suited to substitute the open FICOLL system in bone regeneration procedures.

Magnesium-enriched hydroxyapatite at immediate implants: a histomorphometric study in dogs

Aim To evaluate the influence of magnesium-enriched hydroxyapatite (MHA) (SintLife (R)) on bone contour preservation and osseointegration at implants placed immediately into extraction sockets. Material and methods In the mandibular pre-molar region, implants were installed immediately into extraction sockets of six Labrador dogs. MHA was placed at test sites, while the control sites did not receive augmentation materials. Implants were intended to heal in a submerged mode. After 4 months of healing, the animals were sacrificed, and ground sections were obtained for histomorphometric evaluation. Results After 4 months of healing, one control implant was not integrated leaving n=5 test and control implants for evaluation. Both at the test and the control sites, bone resorption occurred. While the most coronal bone-to-implant contact was similar between test and control sites, the alveolar bony crest outline was maintained to a higher degree at the buccal aspect of the test sites (loss: 0.7 mm) compared with the control sites (loss: 1.2 mm), even though this difference did not reach statistical significance. Conclusions The use of MHA to fill the defect around implants placed into the alveolus immediately after tooth extraction did not contribute significantly to the maintenance of the contours of the buccal alveolar bone crest. To cite this article:Caneva M, Botticelli D, Stellini E, Souza SLS, Salata LA, Lang NP. Magnesium-enriched hydroxyapatite at immediate implants: a histomorphometric study in dogs.Clin. Oral Impl. Res. 22, 2011; 512-517doi: 10.1111/j.1600-0501.2010.02040.x.

Bone Remodeling Adjacent to Morse Cone-Connection Implants with Platform Switch: A Fluorescence Study in the Dog Mandible

Purpose: The aim of this study was to evaluate, through fluorescence analysis, the effect that different interimplant distances, after prosthetic restoration, will have on bone remodeling in submerged and nonsubmerged implants restored with a ""platform switch."" Materials and Methods: Fifty-six Ankylos implants were placed 1.5 mm subcrestally in seven dogs. The implants were placed so that two fixed prostheses, with three interimplant contacts separated by 1-mm, 2-mm, and 3-mm distances, could be fabricated for each side of the mandible. The sides and the positions of the groups were selected randomly. To better evaluate bone remodeling, calcein green was injected 3 days before placement of the prostheses at 12 weeks postimplantation. At 3 days before sacrifice (8 weeks postloading), alizarin red was injected. The amounts of remodeled bone within the different interimplant areas were compared statistically before and after loading in submerged and nonsubmerged implants. Results: Statistically significant differences existed in the percentage of remodeled bone seen in the different regions. Mean percentages of remodeled bone in the submerged and nonsubmerged groups, respectively, were as follows: for the 1-mm distance, 23.0% +/- 0.05% and 23.1% +/- 0.03% preloading and 27.0% +/- 0.03% and 25.2% +/- 0.04% postloading, for the 2-mm distance, 18.2% +/- 0.05% and 18.1% +/- 0.04% preloading and 21.3% +/- 0.07% and 19.9% +/- 0.03% postloading, for the 3-mm distance, 18.3% +/- 0.03% and 18.3% +/- 0.03% preloading and 18.8% +/- 0.04% and 19.8% +/- 0.04% postloading, for distal-extension regions, 16.6% +/- 0.02% and 17.4% +/- 0.04% preloading and 17.0% +/- 0.04% and 18.4% +/- 0.04% postloading. Conclusions: Based upon this animal study, loading increases bone formation for submerged or nonsubmerged implants, and the interimplant distance of 1 mm appears to result in more pronounced bone remodeling than the 2-mm or 3-mm distances in implants with a ""platform switch."" INT J ORAL MAXILLOFAC IMPLANTS 2009;24:257-266

Osteocyte Density in the Peri-Implant Bone of Immediately Loaded and Submerged Dental Implants

Background: The role of osteocytes in bone structure and function remains partially unresolved. Their participation in mechanotransduction, i.e., the conversion of a physical stimulus into a cellular response, has been hypothesized. The present study was an evaluation of the osteocyte density in the peri-implant bone of immediately loaded and submerged dental implants. Methods: Fourteen male patients were included in the study; all of them were partially edentulous and needed a posterior mandibular restoration. Implants were inserted in these areas; half of the sample was loaded immediately (included in a fixed provisional prosthesis on the same day as implant surgery), whereas the other half was left to heal submerged. Fourteen implants (seven immediately loaded and seven unloaded) were retrieved with a trephine after a healing period of 8 weeks. The specimens were treated to obtain thin ground sections, and histomorphometry was used to evaluate the osteocyte index in the peri-implant bone. Results: A higher and statistically significant number of osteocytes was found in the peri-implant bone around immediately loaded implants (P=0.0081). A correlation between the percentage of bone-implant contact and osteocyte density was found for immediately loaded implants (P=0.0480) but not for submerged implants (P=0.2667). Conclusion: The higher number of osteocytes in the peri-implant bone around immediately loaded implants could be related to the functional adaptation required by the loading stimulus, which also explains the hypothesized involvement of the osteocytes in the maintenance of the bone matrix. J Periodontol 2009;80:499-504.

Influence of interimplant distance on bone microstructure: A histomorphometric study in dogs

The microstructure of the crestal alveolar bone is important for both the maintenance of osseointegration and the location of the gingival soft tissues. The aim of this study was to evaluate and compare the bone microstructure of the alveolar bone and of the interimplant bone in implants inserted at different interimplant distances. The mandibular bilateral premolars of six dogs were extracted, and after 12 weeks, each dog received eight implants, for a total of 48 implants. Two pairs of implants, one for each hemiarch, were separated by 2 mm (group 1) and by 3 mm (group 2). After 12 weeks, the implants received temporary acrylic prostheses. After four more weeks, metallic crowns substituted the temporary prostheses. After an additional 8 weeks the animals were sacrificed and the hemimandibles were removed, dissected, and processed. The longitudinal collagen fiber orientation was 43.2% for the alveolar bone; it was 30.3% for the 2-mm group and 43.9% for the 3-mm group. There was a statistically significant difference between the 2-mm and 3-mm groups (p < .05). The orientation of transverse collagen fibers was 47.8% for the alveolar bone; it was 37.3% for the 2-mm group and 56.3% for the 3-mm group. There was a statistically significant difference between the 2-mm and 3-mm groups (p < .05). The marrow spaces were 34.87% for the alveolar bone, 52.3% for the 2-mm group, and 59.9% for the 3-mm group. There was a statistically significant difference between the alveolar bone and the 3-mm group (p < .05). The low mineral density index was 36.29 for the alveolar bone, 46.76 for the 2-mm group, and 17.91 for the 3-mm group. There was a statistically significant difference between the 2-mm and 3-mm groups (p < .05). The high mineral density was 87.57 for the alveolar bone, 72.58 for the 2-mm group, and 84.91 for the 3-mm group. There was a statistically significant difference between the alveolar bone and the 2-mm group (p < .05). The collagen fiber orientation resulted in statistically significant differences in both the 2-mm and 3-mm groups compared with the alveolar bone. The marrow spaces appeared significantly increased in the 3-mm group compared with the alveolar bone. The low mineral density index was significantly higher in the 2-mm group, while the high mineral density index was significantly higher in the alveolar bone. In conclusion, the interimplant distance should not be less than 3 mm.

Effects of Early Functional Loading on Maintenance of Free Autogenous Bone Graft and Implant Osseointegration: An Experimental Study in Dogs

Purpose: The aim of the present study was to investigate the healing, integration, and maintenance of autogenous onlay bone grafts and implant osseointegration either loaded in the early or the delayed stages. Materials and Methods: A total of 5 male clogs received bilateral blocks of onlay bone grafts harvested from the contralateral alveolar ridge of the mandible. On one side, the bone block was secured by 3 dental implants (3.5 mm x 13.0 mm, Osseospeed; Astra Tech AB, Molndal, Sweden). Two implants at the extremities of the graft were loaded 2 clays after installation by abutment connection and prosthesis (simultaneous implant placement group); the implant in the middle remained unloaded and served as the control. On the other side, the block was fixed with 2 fixation screws inserted in the extremities of the graft. Four weeks later, the fixation screws were replaced with 3 dental implants. The loading procedure (delayed implant placement group) was performed 2 clays later, as described for the simultaneous implant placement sites. The animals were sacrificed 12 weeks after the grafting procedure. Implant stability was measured through resonance frequency analysis. The bone volume and density were assessed on computed tomography. The bone to implant contact and bone area in a region of interest were evaluated on histologic slides. Results: The implant stability quotient showed statistical significance in favor of the delayed loaded grafts (P=.001). The bone-to-implant contact (P=.008) and bone area in a region of interest (P=0.005) were significantly greater in the delayed group. Nevertheless, no difference was found in terms of graft volume and density between the early loaded and delayed-loaded approaches. Conclusions: The protocol in which the implant and bone graft were given delayed loading allows for effective quality of implant osseointegration and stabilization, with healing and remodeling occurring in areas near the implant resulting in denser bone architecture. (C) 2010 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Sing 68:825-832, 2010

Bone Formation Following Implantation of Titanium Sponge Rods into Humeral Osteotomies in Dogs: A Histological and Histometrical Study

Background: Titanium (Ti) is widely proven to enhance bone contact and growth on its surface. It is expected that bone defects could benefit from Ti to promote healing and to increase strength of the implanted area. Purpose: The present study aimed at comparing the potential of porous Ti sponge rods with synthetic hydroxyapatite (HA) for the healing of bone defects in a canine model. Material and Methods: Six mongrel dogs were submitted to three trephined osteotomies of 6.0 x 4.0 mm in one humerus and after 2 months another three osteotomies were performed in the contralateral humerus. A total of 36 defects were randomly filled either with Ti foam, particulate HA, or coagulum (control). The six animals were killed 4 months after the first surgery for histological and histometrical analysis. Results: The Ti-foam surface was frequently found in intimate contact with new bone especially at the defect walls. Control sites showed higher amounts of newly formed bone at 2 months - Ti (p = 0.000) and HA (p = 0.009) - and 4 months when compared with Ti (p = 0.001). Differently from HA, the Ti foam was densely distributed across the defect area which rendered less space for bone growth in the latter`s sites. The use of Ti foams or HA resulted in similar amounts of bone formation in both time intervals. Nevertheless, the presence of a Ti-foam rod preserved defect`s marginal bone height as compared with control groups. Also, the Ti-foam group showed a more mature bone pattern at 4 months than HA sites. Conclusion: The Ti foam exhibited good biocompatibility, and its application resulted in improved maintenance of bone height compared with control sites. The Ti foam in a rod design exhibited bone ingrowth properties suitable for further exploration in other experimental situations.

Immunohistochemical, tomographic and histological study on onlay bone graft remodeling. Part II: calvarial bone

Objectives Little information is available on the molecular events that occur during graft incorporation over time. The calvarial bone (Cb) grafts have been reported to produce greater responses compared with other donor regions in maxillofacial reconstructions, but the scientific evidences for this are still lacking. The objectives of this study are (1) to study the morphological pattern of Cb onlay bone grafts and compare them with the biological events through immunohistochemical responses and (2) to establish the effects of perforations in maintaining the volume and bone density of the receptor bed. Material and methods Sixty New Zealand White rabbits were submitted to Cb onlay bone grafts on the mandible. In 30 rabbits, the receptor bed was perforated (perforated group), while for the remaining animals the bed was kept intact (non-perforated group). Six animals from each group were sacrificed at 5, 7, 10, 20 and 60 days after surgery. Histological sections from the grafted area were prepared for immunohistochemical and histological analyses. Immuno-labeling was found for proteins Osteoprotegerin (OPG), receptor activator of nuclear factor-kappa beta ligand (RANKL), alkaline phosphatase (ALP), osteopontin (OPN), vascular endothelial growth factor (VEGF), tartrate-resistant acid phosphatase (TRAP), Type I collagen (COL I) and osteocalcin (OC). The tomography examination [computerized tomography (CT) scan] was conducted just after surgery and at the sacrifice. Results The histological findings revealed that the perforations contributed to higher bone deposition during the initial stages at the graft-receptor bed interface, accelerating the graft incorporation process. The results of the CT scan showed lower resorption for the perforated group (P < 0.05), and both groups showed high bone density rates at 60 days. This set of evidences is corroborated by the immunohistochemical outcomes indicating that proteins associated with revascularization and osteogenesis (VEGF, OPN, TRAP and ALP) were found in higher levels in the perforated group. Conclusions These findings indicate that the bone volume of calvarial grafts is better maintained when the receptor bed is perforated, probably resulting from more effective graft revascularization and greater bone deposition. The process of bone resorption peaked between 20 and 60 days post-operatively in both groups although significantly less in the perforated group. To cite this article:Pedrosa Jr WF, Okamoto R, Faria PEP, Arnez MFM, Xavier SP, Salata LA. Immunohistochemical, tomographic and histological study on onlay bone grafts remodeling. Part II: calvarial bone.Clin. Oral Impl. Res. 20, 2009; 1254-1264.doi: 10.1111/j.1600-0501.2009.01747.x.

Trigeminal nitric oxide synthase expression correlates with new bone formation during distraction osteogenesis

Nitric oxide synthase (NOS) has been reported to be involved with both bone healing and bone metabolism. The aim of this study was to test the null hypothesis that there is no correlation between new bone formation during mandibular distraction osteogenesis and NOS expression in the trigeminal ganglion of rats. Newly formed tissue during distraction osteogenesis and trigeminal NOS expression measured by the NADPH-diaphorase (NADPH-d) reaction were evaluated in 72 male Wistar rats by histomorphometric and histochemical methods. In animals submitted to 0.5 mm/day distraction osteogenesis, the percentage of bone tissue was higher in the basal area of the mandibles compared with the center and significantly increased through the experimental periods (P < 0.05). At the sixth postoperative week, the difference in bone formation between the continuous and acute distraction osteogenesis groups was the highest. Significant correlation between new bone formation by distraction osteogenesis and NADPH-d-reactive neurons was found, varying according to neuronal cell size (r = -0.6, P = 0.005, small cells strongly stained; r = 0.5, P = 0.018, large cells moderately stained). The results suggest that NOS may play a role in the bone healing process via neurogenic pathways, and the phenomenon seems to be neuronal cell morphotype-dependent. Further studies are now warranted to investigate the mechanistic link between the expression of trigeminal NOS and mandibular new bone formation by distraction osteogenesis.

Deiodinase-mediated thyroid hormone inactivation minimizes thyroid hormone signaling in the early development of fetal skeleton

Thyroid hormone (TH) plays a key role on post-natal bone development and metabolism, while its relevance during fetal bone development is uncertain. To Study this, pregnant once were made hypothyroid and fetuses harvested at embryonic days (E) 12.5, 14.5, 16.5 and 18.5. Despite a marked reduction in fetal tissue concentration of both T4 and T3, bone development, as assessed at the distal epiphyseal growth plate of the femur and vertebra, was largely preserved Lip to E16.5. Only at E18.5, the hypothyroid fetuses exhibited a reduction in femoral type I and type X collagen and osteocalcin mRNA levels, in the length and area of the proliferative and hypertrophic zones, in the number of chondrocytes per proliferative column, and in the number of hypertrophic chondrocyres, in addition to a slight delay in endochondral and intramembranous ossification. This Suggests that LIP to E 16.5, thyroid hormone signaling in bone is kept to a minimum. In fact, measuring the expression level of the activating and inactivating iodothyronine deiodinases (D2 and D3) helped understand how this is achieved. D3 mRNA was readily detected as early as E14.5 and its expression decreased markedly (similar to 10-fold) at E18.5, and even more at 14 days after birth (P14). In contrast. D2 mRNA expression increased significantly by E18.5 and markedly (similar to 2.5-fold) by P14. The reciprocal expression levels of D2 and D3 genes during early bone development along with the absence of a hypothyroidism-induced bone phenotype at this time Suggest that coordinated reciprocal deiodinase expression keeps thyroid hormone signaling in bone to very low levels at this early stage of bone development. (c) 2008 Elsevier Inc. All rights reserved.