1 Departments of Cell Biology and Orthopaedics, Yale University School of Medicine, New Haven, Co... more 1 Departments of Cell Biology and Orthopaedics, Yale University School of Medicine, New Haven, Connecticut, USA. 2 Department of Hard Tissue Engineering, Section of Pharmacology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. 3 ...
Transgenic mice overexpressing ΔFosB, a naturally occurring splice variant of FosB, develop an os... more Transgenic mice overexpressing ΔFosB, a naturally occurring splice variant of FosB, develop an osteosclerotic phenotype. The increased bone formation has been shown to be due, at least in part, to autonomous effects of ΔFosB isoforms on cells of the osteoblast lineage. However, abdominal fat and marrow adipocytes are also markedly decreased in ΔFosB mice, leading to low serum leptin levels. Increased bone mass has been linked to the absence of leptin and leptin receptor signaling in ob/ob and db/db mice. Thus, in addition to affecting directly osteoblastogenesis and bone formation, ΔFosB isoforms might increase bone mass indirectly via a decrease in leptin. To test this hypothesis, we restored normal circulating levels of leptin in ΔFosB mice via sc implanted osmotic pumps. Complete histomorphometric analysis demonstrated that trabecular bone volume as well as dynamic parameters of bone formation was unchanged by this treatment in both ΔFosB transgenic mice and control littermates. ...
Growth hormone (GH) regulates both bone growth and remodeling, but it is unclear whether these ac... more Growth hormone (GH) regulates both bone growth and remodeling, but it is unclear whether these actions are mediated directly by the GH receptor (GHR) and/or IGF-I signaling. The actions of GH are transduced by the Jak/Stat signaling pathway via Stat5, which is thought to ...
The protein tyrosine kinase Pyk2 is highly expressed in osteoclasts, where it is primarily locali... more The protein tyrosine kinase Pyk2 is highly expressed in osteoclasts, where it is primarily localized in podosomes. Deletion of Pyk2 in mice leads to mild osteopetrosis due to impairment in osteoclast function. Pyk2-null osteoclasts were unable to transform podosome clusters into a podosome belt at the cell periphery; instead of a sealing zone only small actin rings were formed, resulting in impaired bone resorption. Furthermore, in Pyk2-null osteoclasts, Rho activity was enhanced while microtubule acetylation and stability were significantly reduced. Rescue experiments by ectopic expression of wild-type or a variety of Pyk2 mutants in osteoclasts from Pyk2−/− mice have shown that the FAT domain of Pyk2 is essential for podosome belt and sealing zone formation as well as for bone resorption. These experiments underscore an important role of Pyk2 in microtubule-dependent podosome organization, bone resorption, and other osteoclast functions.
The protein tyrosine kinase Pyk2 is highly expressed in osteoclasts, where it is primarily locali... more The protein tyrosine kinase Pyk2 is highly expressed in osteoclasts, where it is primarily localized in podosomes. Deletion of Pyk2 in mice leads to mild osteopetrosis due to impairment in osteoclast function. Pyk2-null osteoclasts were unable to transform podosome clusters into a podosome belt at the cell periphery; instead of a sealing zone only small actin rings were formed, resulting in impaired bone resorption. Furthermore, in Pyk2-null osteoclasts, Rho activity was enhanced while microtubule acetylation and stability were significantly reduced. Rescue experiments by ectopic expression of wild-type or a variety of Pyk2 mutants in osteoclasts from Pyk2−/− mice have shown that the FAT domain of Pyk2 is essential for podosome belt and sealing zone formation as well as for bone resorption. These experiments underscore an important role of Pyk2 in microtubule-dependent podosome organization, bone resorption, and other osteoclast functions.
Production of the cells that ultimately populate the thymus to generate α/β T cells has been cont... more Production of the cells that ultimately populate the thymus to generate α/β T cells has been controversial, and their molecular drivers remain undefined. Here, we report that specific deletion of bone-producing osteocalcin (Ocn)-expressing cells in vivo markedly reduces T-competent progenitors and thymus-homing receptor expression among bone marrow hematopoietic cells. Decreased intrathymic T cell precursors and decreased generation of mature T cells occurred despite normal thymic function. The Notch ligand DLL4 is abundantly expressed on bone marrow Ocn(+) cells, and selective depletion of DLL4 from these cells recapitulated the thymopoietic abnormality. These data indicate that specific mesenchymal cells in bone marrow provide key molecular drivers enforcing thymus-seeding progenitor generation and thereby directly link skeletal biology to the production of T cell-based adaptive immunity.
The last decade has provided abundant data implicating the WNT pathway in bone development and in... more The last decade has provided abundant data implicating the WNT pathway in bone development and in the regulation of skeletal homeostasis. Rare human mutations together with gain- and loss-of-function approaches in mice have clearly demonstrated that disrupted regulation of this pathway leads to altered bone mass. In addition to these rare human and mice mutations, large population-based genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms in ∼60 loci strongly associated with variations in bone mineral density (BMD) at different skeletal sites. Among the loci/genes identified by BMD GWAS, components of the WNT signaling pathway are numerous and have been shown to contribute to skeletal development and homeostasis. Within the components of WNT signaling, the gene coding for WNT16, one of the 19 WNT ligands of the human genome, has been found strongly associated with specific bone traits such as cortical bone thickness, cortical porosity and fracture risk. Recently, the first functional characterization of Wnt16 has confirmed the critical role of Wnt16 in the regulation of cortical bone mass and bone strength in mice. These reports have extended our understanding of Wnt16 function in bone homeostasis and have not only confirmed the unique association of Wnt16 with cortical bone and fracture susceptibility, as suggested by GWAS in human populations, but have also provided novel insights into the biology of this WNT ligand and the mechanism(s) by which it regulates cortical but not trabecular bone homeostasis. Most interestingly, Wnt16 appears to be a strong anti-resorptive soluble factor acting on both osteoblasts and osteoclast precursors.
Atypical antipsychotic (AA) drugs cause significant metabolic side effects and clinical data are ... more Atypical antipsychotic (AA) drugs cause significant metabolic side effects and clinical data are emerging that demonstrate increased fracture risk and bone loss after treatment with the AA, risperidone (RIS). The pharmacology underlying the adverse effects on bone is unknown. However, RIS action in the central nervous system (CNS) could be responsible because the sympathetic nervous system (SNS) is known to uncouple bone remodeling. RIS treatment in mice significantly lowered trabecular bone volume fraction (BV/TV), due to increased osteoclast-mediated erosion and reduced osteoblast-mediated bone formation. Daytime energy expenditure was also increased and was temporally associated with the plasma concentration of RIS. Even a single dose of RIS transiently elevated expression of brown adipose tissue markers of SNS activity and thermogenesis, Pgc1a and Ucp1. Rankl, an osteoclast recruitment factor regulated by the SNS, was also increased 1 hr after a single dose of RIS. Thus, we infe...
Alveolar bone normally undergoes remodeling on one side of the socket and modeling on the opposit... more Alveolar bone normally undergoes remodeling on one side of the socket and modeling on the opposite side as the tooth migrates at a rate of 6.7 micrometer per day. Periodontal ligament width, however, remains constant. Because of this very high turnover rate, this bone is a good model to study bone modeling and remodeling activities. This study was undertaken in order to measure the different cellular events occurring during tooth migration along the alveolar bone of the rat. The histomorphometric measurements performed on this model permitted us to calculate the duration of each phase of the remodeling cycle, i.e., resorption lasts about 1.5 days and reversal about 3.5 days. Since the duration of the forming phase is about 1 day (Guyomard and Baron, '74), the total duration of each remodeling cycle is about 6 days. This time is very short compared to 60--120 days in adult human trabecular bone. Additionally, in this model each osteoclast resorbs 2--4 times its own volume of bone...
Imbalances in the ratio of bone morphogenetic protein (BMP) versus activin and TGFβ signaling are... more Imbalances in the ratio of bone morphogenetic protein (BMP) versus activin and TGFβ signaling are increasingly associated with human diseases yet the mechanisms mediating this relationship remain unclear. The type 2 receptors ACVR2A and ACVR2B bind BMPs and activins but the type 2 receptor BMPR2 only binds BMPs, suggesting that type 2 receptor utilization might play a role in mediating the interaction of these pathways. We tested this hypothesis in the mouse skeleton, where bone mass is reciprocally regulated by BMP signaling and activin and TGFβ signaling. We found that deleting Bmpr2 in mouse skeletal progenitor cells (Bmpr2-cKO mice) selectively impaired activin signaling but had no effect on BMP signaling, resulting in an increased bone formation rate and high bone mass. Additionally, activin sequestration had no effect on bone mass in Bmpr2-cKO mice but increased bone mass in wild-type mice. Our findings suggest a novel model whereby BMPR2 availability alleviates receptor-level...
The mTOR pathway couples energy homeostasis to growth, division and survival of the cell. Stk11/L... more The mTOR pathway couples energy homeostasis to growth, division and survival of the cell. Stk11/Lkb1 is a critical serine-threonine protein kinase in the inhibition of mTOR pathway action. In the mammalian skeleton, Stk11 regulates the transition between immature and hypertrophic chondrocytes. Here, we have focused on the action of Stk11in the osteoblast lineage through osteoblast specific-removal of Stk11 activity. In the mouse model system, specification and primary organization of the neonatal boney skeleton is independent of Stk11. However, histological, molecular and micro-CT analysis revealed a marked perturbation of normal bone development evident in the immediate post-natal period. Cortical bone was unusually porous displaying a high rate of turnover with new trabeculae forming in the endosteal space. Trabecular bone also showed enhanced turnover and marked increase in the density of trabeculae and number of osteoclasts. Though mutants showed an expansion of bone volume and ...
Lactation is associated with significant alterations in both body composition and bone mass. Syst... more Lactation is associated with significant alterations in both body composition and bone mass. Systemic and local skeletal factors such as receptor activator of nuclear factor κ-B ligand (RANKL), PTHrP, calcitonin, and estrogen are known to regulate bone remodeling during and after lactation. Fibroblast growth factor 21 (FGF-21) may function as an endocrine factor to regulate body composition changes during lactation by inducing gluconeogenesis and fatty acid oxidation. In this study, we hypothesized that the metabolic changes during lactation were due in part to increased circulating FGF-21, which in turn could accentuate bone loss. We longitudinally characterized body composition in C57BL/6J (B6) mice during (day 7 and day 21 of lactation) and after normal lactation (day 21 postlactation). At day 7 of lactation, areal bone density declined by 10% (P < .001), bone resorption increased (P < .0001), percent fat decreased by 20%, energy expenditure increased (P < .01), and mark...
Biochemical and Biophysical Research Communications, 2002
The Src-SH2 domain has been determined to play a key role in many signaling pathways, especially ... more The Src-SH2 domain has been determined to play a key role in many signaling pathways, especially in osteoclast-mediated bone resorption. Therefore, non-peptidic small molecules, mimicking the natural pYEEI peptide ligand, have been designed, to inhibit SH2-mediated protein–protein interactions and provide therapeutic treatment of certain diseases such as osteoporosis. However it has been shown in vitro that phosphopeptidic ligands of the
THE primary defect in mice lacking the c-src gene is osteopetrosis, a deficiency in bone resorpti... more THE primary defect in mice lacking the c-src gene is osteopetrosis, a deficiency in bone resorption by osteoclasts1. Osteoclasts express high levels of the c-Src protein2,3 and the defect responsible for the osteopetrotic phenotype of the c-src-deficient (src-) mouse is cell-autonomous and occurs in mature osteoclasts4,5. However, the specific signalling pathways that require c-Src expression for normal osteoclast activity have
The effects of retinoids, the structural derivatives of vitamin A (retinol), on post-natal peak b... more The effects of retinoids, the structural derivatives of vitamin A (retinol), on post-natal peak bone density acquisition and skeletal remodeling are complex and compartment specific. Emerging data indicates that retinoids, such as all trans retinoic acid (ATRA) and its precursor all trans retinaldehyde (Rald), exhibit distinct and divergent transcriptional effects in metabolism. Despite these observations, the role of enzymes that control retinoid metabolism in bone remains undefined. In this study, we examined the skeletal phenotype of mice deficient in retinaldehyde dehydrogenase 1 (Aldh1a1), the enzyme responsible for converting Rald to ATRA in adult animals. Bone densitometry and micro-computed tomography (µCT) demonstrated that Aldh1a1-deficient (Aldh1a1(-/-) ) female mice had higher trabecular and cortical bone mass compared to age and sex-matched control C57Bl/6 wild type (WT) mice at multiple time points. Histomorphometry confirmed increased cortical bone thickness and demon...
We have investigated the effect of 1-(5-oxohexyl)-3,7-dimeth- ylxanthine or pentoxifylline (PeTx)... more We have investigated the effect of 1-(5-oxohexyl)-3,7-dimeth- ylxanthine or pentoxifylline (PeTx), a nonselective phospho- diesterase inhibitor, on osteoblastic differentiation in vitro by using two mesenchymal cell lines, C3H10T1/2 and C2C12, which are able to acquire the osteoblastic phenotype in the presence of bone morphogenetic protein-2 (BMP-2). PeTx in- duced the osteoblastic markers, osteocalcin and Osf2/Cbfa1, in C3H10T1/2 and C2C12 cells
1 Departments of Cell Biology and Orthopaedics, Yale University School of Medicine, New Haven, Co... more 1 Departments of Cell Biology and Orthopaedics, Yale University School of Medicine, New Haven, Connecticut, USA. 2 Department of Hard Tissue Engineering, Section of Pharmacology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. 3 ...
Transgenic mice overexpressing ΔFosB, a naturally occurring splice variant of FosB, develop an os... more Transgenic mice overexpressing ΔFosB, a naturally occurring splice variant of FosB, develop an osteosclerotic phenotype. The increased bone formation has been shown to be due, at least in part, to autonomous effects of ΔFosB isoforms on cells of the osteoblast lineage. However, abdominal fat and marrow adipocytes are also markedly decreased in ΔFosB mice, leading to low serum leptin levels. Increased bone mass has been linked to the absence of leptin and leptin receptor signaling in ob/ob and db/db mice. Thus, in addition to affecting directly osteoblastogenesis and bone formation, ΔFosB isoforms might increase bone mass indirectly via a decrease in leptin. To test this hypothesis, we restored normal circulating levels of leptin in ΔFosB mice via sc implanted osmotic pumps. Complete histomorphometric analysis demonstrated that trabecular bone volume as well as dynamic parameters of bone formation was unchanged by this treatment in both ΔFosB transgenic mice and control littermates. ...
Growth hormone (GH) regulates both bone growth and remodeling, but it is unclear whether these ac... more Growth hormone (GH) regulates both bone growth and remodeling, but it is unclear whether these actions are mediated directly by the GH receptor (GHR) and/or IGF-I signaling. The actions of GH are transduced by the Jak/Stat signaling pathway via Stat5, which is thought to ...
The protein tyrosine kinase Pyk2 is highly expressed in osteoclasts, where it is primarily locali... more The protein tyrosine kinase Pyk2 is highly expressed in osteoclasts, where it is primarily localized in podosomes. Deletion of Pyk2 in mice leads to mild osteopetrosis due to impairment in osteoclast function. Pyk2-null osteoclasts were unable to transform podosome clusters into a podosome belt at the cell periphery; instead of a sealing zone only small actin rings were formed, resulting in impaired bone resorption. Furthermore, in Pyk2-null osteoclasts, Rho activity was enhanced while microtubule acetylation and stability were significantly reduced. Rescue experiments by ectopic expression of wild-type or a variety of Pyk2 mutants in osteoclasts from Pyk2−/− mice have shown that the FAT domain of Pyk2 is essential for podosome belt and sealing zone formation as well as for bone resorption. These experiments underscore an important role of Pyk2 in microtubule-dependent podosome organization, bone resorption, and other osteoclast functions.
The protein tyrosine kinase Pyk2 is highly expressed in osteoclasts, where it is primarily locali... more The protein tyrosine kinase Pyk2 is highly expressed in osteoclasts, where it is primarily localized in podosomes. Deletion of Pyk2 in mice leads to mild osteopetrosis due to impairment in osteoclast function. Pyk2-null osteoclasts were unable to transform podosome clusters into a podosome belt at the cell periphery; instead of a sealing zone only small actin rings were formed, resulting in impaired bone resorption. Furthermore, in Pyk2-null osteoclasts, Rho activity was enhanced while microtubule acetylation and stability were significantly reduced. Rescue experiments by ectopic expression of wild-type or a variety of Pyk2 mutants in osteoclasts from Pyk2−/− mice have shown that the FAT domain of Pyk2 is essential for podosome belt and sealing zone formation as well as for bone resorption. These experiments underscore an important role of Pyk2 in microtubule-dependent podosome organization, bone resorption, and other osteoclast functions.
Production of the cells that ultimately populate the thymus to generate α/β T cells has been cont... more Production of the cells that ultimately populate the thymus to generate α/β T cells has been controversial, and their molecular drivers remain undefined. Here, we report that specific deletion of bone-producing osteocalcin (Ocn)-expressing cells in vivo markedly reduces T-competent progenitors and thymus-homing receptor expression among bone marrow hematopoietic cells. Decreased intrathymic T cell precursors and decreased generation of mature T cells occurred despite normal thymic function. The Notch ligand DLL4 is abundantly expressed on bone marrow Ocn(+) cells, and selective depletion of DLL4 from these cells recapitulated the thymopoietic abnormality. These data indicate that specific mesenchymal cells in bone marrow provide key molecular drivers enforcing thymus-seeding progenitor generation and thereby directly link skeletal biology to the production of T cell-based adaptive immunity.
The last decade has provided abundant data implicating the WNT pathway in bone development and in... more The last decade has provided abundant data implicating the WNT pathway in bone development and in the regulation of skeletal homeostasis. Rare human mutations together with gain- and loss-of-function approaches in mice have clearly demonstrated that disrupted regulation of this pathway leads to altered bone mass. In addition to these rare human and mice mutations, large population-based genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms in ∼60 loci strongly associated with variations in bone mineral density (BMD) at different skeletal sites. Among the loci/genes identified by BMD GWAS, components of the WNT signaling pathway are numerous and have been shown to contribute to skeletal development and homeostasis. Within the components of WNT signaling, the gene coding for WNT16, one of the 19 WNT ligands of the human genome, has been found strongly associated with specific bone traits such as cortical bone thickness, cortical porosity and fracture risk. Recently, the first functional characterization of Wnt16 has confirmed the critical role of Wnt16 in the regulation of cortical bone mass and bone strength in mice. These reports have extended our understanding of Wnt16 function in bone homeostasis and have not only confirmed the unique association of Wnt16 with cortical bone and fracture susceptibility, as suggested by GWAS in human populations, but have also provided novel insights into the biology of this WNT ligand and the mechanism(s) by which it regulates cortical but not trabecular bone homeostasis. Most interestingly, Wnt16 appears to be a strong anti-resorptive soluble factor acting on both osteoblasts and osteoclast precursors.
Atypical antipsychotic (AA) drugs cause significant metabolic side effects and clinical data are ... more Atypical antipsychotic (AA) drugs cause significant metabolic side effects and clinical data are emerging that demonstrate increased fracture risk and bone loss after treatment with the AA, risperidone (RIS). The pharmacology underlying the adverse effects on bone is unknown. However, RIS action in the central nervous system (CNS) could be responsible because the sympathetic nervous system (SNS) is known to uncouple bone remodeling. RIS treatment in mice significantly lowered trabecular bone volume fraction (BV/TV), due to increased osteoclast-mediated erosion and reduced osteoblast-mediated bone formation. Daytime energy expenditure was also increased and was temporally associated with the plasma concentration of RIS. Even a single dose of RIS transiently elevated expression of brown adipose tissue markers of SNS activity and thermogenesis, Pgc1a and Ucp1. Rankl, an osteoclast recruitment factor regulated by the SNS, was also increased 1 hr after a single dose of RIS. Thus, we infe...
Alveolar bone normally undergoes remodeling on one side of the socket and modeling on the opposit... more Alveolar bone normally undergoes remodeling on one side of the socket and modeling on the opposite side as the tooth migrates at a rate of 6.7 micrometer per day. Periodontal ligament width, however, remains constant. Because of this very high turnover rate, this bone is a good model to study bone modeling and remodeling activities. This study was undertaken in order to measure the different cellular events occurring during tooth migration along the alveolar bone of the rat. The histomorphometric measurements performed on this model permitted us to calculate the duration of each phase of the remodeling cycle, i.e., resorption lasts about 1.5 days and reversal about 3.5 days. Since the duration of the forming phase is about 1 day (Guyomard and Baron, '74), the total duration of each remodeling cycle is about 6 days. This time is very short compared to 60--120 days in adult human trabecular bone. Additionally, in this model each osteoclast resorbs 2--4 times its own volume of bone...
Imbalances in the ratio of bone morphogenetic protein (BMP) versus activin and TGFβ signaling are... more Imbalances in the ratio of bone morphogenetic protein (BMP) versus activin and TGFβ signaling are increasingly associated with human diseases yet the mechanisms mediating this relationship remain unclear. The type 2 receptors ACVR2A and ACVR2B bind BMPs and activins but the type 2 receptor BMPR2 only binds BMPs, suggesting that type 2 receptor utilization might play a role in mediating the interaction of these pathways. We tested this hypothesis in the mouse skeleton, where bone mass is reciprocally regulated by BMP signaling and activin and TGFβ signaling. We found that deleting Bmpr2 in mouse skeletal progenitor cells (Bmpr2-cKO mice) selectively impaired activin signaling but had no effect on BMP signaling, resulting in an increased bone formation rate and high bone mass. Additionally, activin sequestration had no effect on bone mass in Bmpr2-cKO mice but increased bone mass in wild-type mice. Our findings suggest a novel model whereby BMPR2 availability alleviates receptor-level...
The mTOR pathway couples energy homeostasis to growth, division and survival of the cell. Stk11/L... more The mTOR pathway couples energy homeostasis to growth, division and survival of the cell. Stk11/Lkb1 is a critical serine-threonine protein kinase in the inhibition of mTOR pathway action. In the mammalian skeleton, Stk11 regulates the transition between immature and hypertrophic chondrocytes. Here, we have focused on the action of Stk11in the osteoblast lineage through osteoblast specific-removal of Stk11 activity. In the mouse model system, specification and primary organization of the neonatal boney skeleton is independent of Stk11. However, histological, molecular and micro-CT analysis revealed a marked perturbation of normal bone development evident in the immediate post-natal period. Cortical bone was unusually porous displaying a high rate of turnover with new trabeculae forming in the endosteal space. Trabecular bone also showed enhanced turnover and marked increase in the density of trabeculae and number of osteoclasts. Though mutants showed an expansion of bone volume and ...
Lactation is associated with significant alterations in both body composition and bone mass. Syst... more Lactation is associated with significant alterations in both body composition and bone mass. Systemic and local skeletal factors such as receptor activator of nuclear factor κ-B ligand (RANKL), PTHrP, calcitonin, and estrogen are known to regulate bone remodeling during and after lactation. Fibroblast growth factor 21 (FGF-21) may function as an endocrine factor to regulate body composition changes during lactation by inducing gluconeogenesis and fatty acid oxidation. In this study, we hypothesized that the metabolic changes during lactation were due in part to increased circulating FGF-21, which in turn could accentuate bone loss. We longitudinally characterized body composition in C57BL/6J (B6) mice during (day 7 and day 21 of lactation) and after normal lactation (day 21 postlactation). At day 7 of lactation, areal bone density declined by 10% (P < .001), bone resorption increased (P < .0001), percent fat decreased by 20%, energy expenditure increased (P < .01), and mark...
Biochemical and Biophysical Research Communications, 2002
The Src-SH2 domain has been determined to play a key role in many signaling pathways, especially ... more The Src-SH2 domain has been determined to play a key role in many signaling pathways, especially in osteoclast-mediated bone resorption. Therefore, non-peptidic small molecules, mimicking the natural pYEEI peptide ligand, have been designed, to inhibit SH2-mediated protein–protein interactions and provide therapeutic treatment of certain diseases such as osteoporosis. However it has been shown in vitro that phosphopeptidic ligands of the
THE primary defect in mice lacking the c-src gene is osteopetrosis, a deficiency in bone resorpti... more THE primary defect in mice lacking the c-src gene is osteopetrosis, a deficiency in bone resorption by osteoclasts1. Osteoclasts express high levels of the c-Src protein2,3 and the defect responsible for the osteopetrotic phenotype of the c-src-deficient (src-) mouse is cell-autonomous and occurs in mature osteoclasts4,5. However, the specific signalling pathways that require c-Src expression for normal osteoclast activity have
The effects of retinoids, the structural derivatives of vitamin A (retinol), on post-natal peak b... more The effects of retinoids, the structural derivatives of vitamin A (retinol), on post-natal peak bone density acquisition and skeletal remodeling are complex and compartment specific. Emerging data indicates that retinoids, such as all trans retinoic acid (ATRA) and its precursor all trans retinaldehyde (Rald), exhibit distinct and divergent transcriptional effects in metabolism. Despite these observations, the role of enzymes that control retinoid metabolism in bone remains undefined. In this study, we examined the skeletal phenotype of mice deficient in retinaldehyde dehydrogenase 1 (Aldh1a1), the enzyme responsible for converting Rald to ATRA in adult animals. Bone densitometry and micro-computed tomography (µCT) demonstrated that Aldh1a1-deficient (Aldh1a1(-/-) ) female mice had higher trabecular and cortical bone mass compared to age and sex-matched control C57Bl/6 wild type (WT) mice at multiple time points. Histomorphometry confirmed increased cortical bone thickness and demon...
We have investigated the effect of 1-(5-oxohexyl)-3,7-dimeth- ylxanthine or pentoxifylline (PeTx)... more We have investigated the effect of 1-(5-oxohexyl)-3,7-dimeth- ylxanthine or pentoxifylline (PeTx), a nonselective phospho- diesterase inhibitor, on osteoblastic differentiation in vitro by using two mesenchymal cell lines, C3H10T1/2 and C2C12, which are able to acquire the osteoblastic phenotype in the presence of bone morphogenetic protein-2 (BMP-2). PeTx in- duced the osteoblastic markers, osteocalcin and Osf2/Cbfa1, in C3H10T1/2 and C2C12 cells
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Papers by Roland Baron