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The art of building bone: emerging role of chondrocyte-to-osteoblast transdifferentiation in endochondral ossification

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Bone Research 2018年第3期6卷 217-225页

作者： Patrick Aghajanian subburaman mohan Musculoskeletal Disease Center Veterans Affairs Loma Linda Healthcare System Department of Medicine Loma Linda University Department of Orthopedics Loma Linda University Department of Biochemistry Loma Linda University

There is a worldwide epidemic of skeletal diseases causing not only a public health issue but also accounting for a sizable portion of healthcare expenditures. The vertebrate skeleton is known to be formed by mesenchymal cells condensing into tissue elements(patterning phase) followed by their differentiation into cartilage(chondrocytes) or bone(osteoblasts) cells within the condensations. During the growth and remodeling phase, bone is formed directly via intramembranous ossification or through a cartilage to bone conversion via endochondral ossification routes. The canonical pathway of the endochondral bone formation process involves apoptosis of hypertrophic chondrocytes followed by vascular invasion that brings in osteoclast precursors to remove cartilage and osteoblast precursors to form bone. However, there is now an emerging role for chondrocyte-to-osteoblast transdifferentiation in the endochondral ossification process. Although the concept of "transdifferentiation" per se is not recent,new data using a variety of techniques to follow the fate of chondrocytes in different bones during embryonic and post-natal growth as well as during fracture repair in adults have identified three different models for chondrocyte-to-osteoblast transdifferentiation(direct transdifferentiation, dedifferentiation to redifferentiation, and chondrocyte to osteogenic precursor). This review focuses on the emerging models of chondrocyte-to-osteoblast transdifferentiation and their implications for the treatment of skeletal diseases as well as the possible signaling pathways that contribute to chondrocyte-to-osteoblast transdifferentiation processes.

关键词： cartilage(chondrocytes)or bone(osteoblasts) chondrocyte-to-osteoblast

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Role and Mechanisms of Actions of Thyroid Hormone on the Skeletal Development

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Bone Research 2013年第2期1卷 146-161页

作者： Ha-Young Kim subburaman mohan Musculoskeletal Disease Center Loma Linda VA HealthCare System Departments of Medicine Loma Linda University Division of Endocrinology Department of Internal MedicineWonkwang University Sanbon Hospital

The importance of the thyroid hormone axis in the regulation of skeletal growth and maintenance has been well established from clinical studies involving patients with mutations in proteins that regulate synthesis and/or actions of thyroid hormone. Data from genetic mouse models involving disruption and overexpression of components of the thyroid hormone axis also provide direct support for a key role for thyroid hormone in the regulation of bone metabolism. Thyroid hormone regulates proliferation and/or differentiated actions of multiple cell types in bone including chondrocytes, osteoblasts and osteoclasts. Thyroid hormone effects on the target cells are mediated via ligand-inducible nuclear receptors/transcription factors, thyroid hormone receptor （TR） a and ~, of which TRa seems to be critically important in regulating bone cell functions. In terms of mechanisms for thyroid hormone action, studies suggest that thyroid hormone regulates a number of key growth factor signaling pathways including insulin-like growth factor-I, parathyroid hormone related protein, fibroblast growth factor, Indian hedgehog and Wnt to influence skeletal growth. In this review we describe findings from various genetic mouse models and clinical mutations of thyroid hormone signaling related mutations in humans that pertain to the role and mechanism of action of thyroid hormone in the regulation of skeletal growth and maintenance.

关键词： thyroid hormone bone cartilage growth factors bone cells

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维普期刊数据库

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Conditional disruption of the osterix gene in chondrocytes during early postnatal growth impairs secondary ossification in the mouse tibial epiphysis

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Bone Research 2019年第3期7卷 310-317页

作者： Weirong Xing Catrina Godwin Sheila Pourteymoor subburaman mohan 1Musculoskeletal Disease Center VA Loma Linda Healthcare System Loma Linda CA 92357 USA Department of Medicine Loma Linda University Loma Linda CA 92357 USA Department of Orthopedics Loma Linda University Loma Linda CA 92357 USA Department of Biochemistry Loma Linda University Loma Linda CA 92357 USA

In our previous studies, we have found that the prepubertal increase in thyroid hormone levels induces osterix(Osx) signaling in hypertrophic chondrocytes to transdifferentiate them into osteoblasts. To test if Osx expressed in chondrocytes directly contributes to transdifferentiation and secondary ossification, we generated Osx^flox/flox;Col2-Cre-ERT2 mice and knocked out Osx with a single injection of tamoxifen at postnatal day(P) 3 prior to evaluation of the epiphyseal bone phenotype by μCT, histology, and immunohistochemistry(IHC) at P21. Vehicle(oil)-treated Osx^flox/flox;Col2-Cre-ERT2 and tamoxifen-treated, Cre-negative Osx^flox/flox mice were used as controls.μCT analysis of tibial epiphyses revealed that trabecular bone mass was reduced by 23% in the Osx conditional knockout(c KO) compared with control mice. Trabecular number and thickness were reduced by 28% and 8%,respectively, while trabecular separation was increased by 24% in the c KO mice. Trichrome staining of longitudinal sections of tibial epiphyses showed that bone area and bone area adjusted for total area were decreased by 22% and 18%, respectively. IHC studies revealed the presence of abundant Osx-expressing prehypertrophic chondrocytes in the epiphyses of control mice at P10, but not in the cKO mice. Furthermore, expression levels of MMP13, COL10, ALP, and BSP were considerably reduced in the epiphyses of cKO mice. We also found that Osx overexpression in ATDC5 chondrocytes increased expression of Col10, Mmp13, Alp, and Bsp. Our data indicate that Osx expressed in chondrocytes plays a significant role in secondary ossification by regulating expression of genes involved in chondrocyte hypertrophy and osteoblast transdifferentiation.

关键词： ossification thyroid hormone Large chondrocyte

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Role and mechanism of action of leucine-rich repeat kinase 1 in bone

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Bone Research 2017年第1期5卷 14-26页

作者： Weirong Xing Helen Goodluck Canjun Zeng subburaman mohan Musculoskeletal Disease Center Jerry L.Pettis Memorial VA Medical CenterLoma LindaCAUSA Department of Medicine Loma Linda UniversityLoma LindaCAUSA Department of Orthopedics The Third Affiliated Hospital of Southern Medical UniversityGuangzhouChina

Leucine-rich repeat kinase 1 （LRRK1） plays a critical role in regulating cytoskeletal organization, osteoclast activity, and bone resorption with little effect on bone formation parameters. Deficiency of Lrrkl in mice causes a severe osteopetrosis in the metaphysis of the long bones and vertebrae bones, which makes LRRK1 an attractive alternative drug target for the treatment of osteoporosis and other high-turnover bone diseases. This review recent advances on the functions of the Lrrkl-related family members, Lrrkl deficiency-induced skeletal phenotypes, LRRK1 structure-function, potential biological substrates and interacting proteins, and the mechanisms of LRRK1 action in osteoclasts.

关键词： gene Role and mechanism of action of leucine-rich repeat kinase 1 in bone

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Experimental repetitive mild traumatic brain injury induces deficits in trabecular bone microarchitecture and strength in mice

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Bone Research 2017年第4期5卷 357-366页

作者： Chandrasekhar Kesavan Nikita M Bajwa Heather Watt subburaman mohan Musculoskeletal Disease Center VA Loma Linda Healthcare SystemLama LindaCAUSA Department of Medicine Loma DndaCAUSA Department of Orthopedic Surgery Loma Linda UniversityLoma LindaCAUSA

To evaluate the long-term consequence of repetitive mild traumatic brain injury （mTBI） on bone, mTBI was induced in 10-week-old female C57BL/6J mice using a weight drop model, once per day for 4 consecutive days at different drop heights （0.5, 1 and 1.5 m） and the skeletal phenotype was evaluated at different time points after the impact. In vivo micro-CT （μ-CT） analysis of the tibial metaphysis at 2, 8 and 12 weeks after the impact revealed a 5%-32% reduction in trabecular bone mass. Histomorphometric analyses showed a reduced bone formation rate in the secondary spongiosa ofl.5 m impacted mice at 12 weeks post impact. Apparent modulus （bone strength）, was reduced by 30% （P 〈 0.05） at the proximal tibial metaphysis in the 1.5 m drop height group at 2 and 8 weeks post impact. Ex vivo μ-CT analysis of the fifth lumbar vertebra revealed a significant reduction in trabecular bone mass at 12 weeks of age in all three drop height groups. Serum levels of osteocalcin were decreased by 22%, 15%, and 19% in the 0.5, 1.0 and 1.5 m drop height groups, respectively, at 2 weeks post impact. Serum IGF-I levels were reduced by 18%-32% in mTBI mice compared to control mice at 2 weeks post impact. Serum osteocalcin and IGF-I levels correlated with trabecular BV/TV （r2 = 0.14 and 0.16, P 〈 0.05）. In conclusion, repetitive mTBI exerts significant negative effects on the trabecular bone microarchitecture and bone mechanical properties by influencing osteoblast function via reduced endocrine IGF-I actions.

关键词： IGF TBI Experimental repetitive mild traumatic brain injury induces deficits in trabecular bone microarchitecture and strength in mice

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A segmental defect adaptation of the mouse closed femur fracture model for the analysis of severely impaired bone healing

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Animal Models and Experimental Medicine 2020年第2期3卷 130-139页

作者： Amandeep Kaur subburaman mohan Charles H.Rundle Musculoskeletal Disease Center Research Service(151)Jerry L.Pettis Memorial Veterans Administration Medical CenterLoma LindaCAUSA Department of Medicine Loma Linda UniversityLoma LindaCAUSA Department of Orthopedic Surgery Loma Linda UniversityLoma LindaCAUSA

Objective: To better characterize nonunion endochondral bone healing and evaluate novel therapeutic approaches for critical size defect healing in clinically challenging bone repair, a segmental defect model of bone injury was adapted from the threepoint bending closed fracture technique in the murine ***: The mouse femur was surgically stabilized with an intramedullary threaded rod with plastic spacers and the defect adjusted to different sizes. Healing of the different defects was analyzed by radiology and histology to 8 weeks postsurgery. To determine whether this model was effective for evaluating the benefits of molecular therapy, BMP-2 was applied to the defect and healing then ***: Intramedullary spacers were effective in maintaining the defect. Callus bone formation was initiated but was arrested at defect sizes of 2.5 mm and above, with no more progress in callus bone development evident to 8 weeks healing. Cartilage development in a critical size defect attenuated very early in healing without bone development, in contrast to the closed femur fracture healing, where callus cartilage was replaced by bone. BMP-2 therapy promoted osteogenesis of the resident cells of the defect, but there was no further callus development to indicate that healing to pre-surgery bone structure was ***: This segmental defect adaptation of the closed femur fracture model of murine bone repair severely impairs callus development and bone healing, reflecting a challenging bone injury. It is adjustable and can be compared to the closed fracture model to ascertain healing deficiencies and the efficacy of therapeutic approaches.

关键词： bone fractures bone morphogenetic protein 2 intramedullary fracture fixation ununited fractures

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In vivo evidence of IGF-I–estrogen crosstalk in mediating the cortical bone response to mechanical strain

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Bone Research 2014年第1期2卷 55-60页

作者： subburaman mohan Chetan Girijanand Bhat Jon E Wergedal Chandrasekhar Kesavan Musculoskeletal Disease Center VA Loma Linda Healthcare System Department of Medicine Loma Linda University Department of Biochemistry Loma Linda University Department of Physiology Loma Linda University

Although insulin-like growth factor-I （IGF-I） and estrogen signaling pathways have been shown to be involved in mediating the bone anabolic response to mechanical loading, it is not known whether these two signaling pathways crosstalk with each other in producing a skeletal response to mechanical loading. To test this, at 5 weeks of age, partial ovariectomy （pOVX） or a sham operation was performed on heterozygous IGF-I conditional knockout （H IGF-I KO） and control mice generated using a Cre-loxP approach. At 10 weeks of age, a 10 N axial load was applied on the right tibia of these mice for a period of 2 weeks and the left tibia was used as an internal non-non-loaded control. At the cortical site, partial estrogen loss reduced total volumetric bone mineral density （BMD） by 5% in control pOVX mice （P=0.05, one-way ANOVA）, but not in the H IGF-I KO pOVX mice. At the trabecular site, bone volume/total volume （BV/TV） was reduced by 5%-6% in both control pOVX （P〈0.05） and H IGF-I KO pOVX （P=0.05） mice. Two weeks of mechanical loading caused a 7 %-8% and an 11%-13% （P〈0.05 vs. non-loaded bones） increase in cortical BMD and cortical thickness （***）, respectively, in the control sham, control pOVX and H IGF-I KO sham groups. By contrast, the magnitude of cortical BMD （4%, P=0.13） and *** （6%, P〈0.05） responses were reduced by 50% in the H IGF-I KO pOVX mice compared to the other three groups. The interaction between genotype and estrogen deficiency on the mechanical loading-induced cortical bone response was significant （P〈0.05） by two-way ANOVA. Two weeks of axial loading caused similar increases in trabecular BV/TV （13%-17%） and thickness （17%-23%） in all four groups of mice. In conclusion, partial loss of both estrogen and IGF-I significantly reduced cortical but not the trabecular bone response to mechanical loading, providing in vivo evidence of the above crosstalk in mediating the bone response to loading.

关键词： bone IGF estrogen crosstalk in mediating the cortical bone response to mechanical strain

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Model-based Comparative Prediction of Transcription-Factor Binding Motifs in Anabolic Responses in Bone

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Genomics, Proteomics & Bioinformatics 2007年第3期5卷 158-165页

作者： Andy B. Chen Kazunori Hamamura Guohua Wang Weirong Xing subburaman mohan Hiroki Yokota Yunlong Liu Departments of Biomedical Engineering/Anatomy and Cell Biology Indiana University-Purdue University Indianapolis Indianapolis IN 45202 USA Division of Biostatistics Department of Medicine Center for Computational Biology and Bioinformatics Indiana University School of Medicine Indianapolis IN 46202 USA School of Computer Science and Technology Harbin Institute of Technology Harbin 150001 China Musculoskeletal Disease Center JP Pettis Memorial Veterans Administration Medical Center Loma Linda CA 92357 USA

Understanding the regulatory mechanism that controls the alteration of global gene expression patterns continues to be a challenging task in computational biology. We previously developed an ant algorithm, a biologically-inspired computational technique for microarray data, and predicted putative transcription-factor binding motifs （TFBMs） through mimicking interactive behaviors of natural ants. Here we extended the algorithm into a set of web-based software, Ant Modeler, and applied it to investigate the transcriptional mechanism underlying bone formation. Mechanical loading and administration of bone morphogenic proteins （BMPs） are two known treatments to strengthen bone. We addressed a question： Is there any TFBM that stimulates both ＂anabolic responses of mechanical loading＂ and ＂BMP-mediated osteogenic signaling＂？ Although there is no significant overlap among genes in the two responses, a comparative model-based analysis suggests that the two independent osteogenic processes employ common TFBMs, such as a stress responsive element and a motif for peroxisome proliferator-activated receptor （PPAR）. The post-modeling in vitro analysis using mouse osteoblast cells supported involvements of the predicted TFBMs such as PPAR, Ikaros 3, and LMO2 in response to mechanical loading. Taken together, the results would be useful to derive a set of testable hypotheses and examine the role of specific regulators in complex transcriptional control of bone formation.

关键词： microarray transcription-factor binding motif mechanical loading bone morphogenic protein ant algorithm

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