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Rosa Chung and Cory J Xian

Injuries to the growth plate cartilage often lead to bony repair, resulting in bone growth defects such as limb length discrepancy and angulation deformity in children. Currently utilised corrective surgeries are highly invasive and limited in their effectiveness, and there are no known biological therapies to induce cartilage regeneration and prevent the undesirable bony repair. In the last 2 decades, studies have investigated the cellular and molecular events that lead to bony repair at the injured growth plate including the identification of the four phases of injury repair responses (inflammatory, fibrogenic, osteogenic and remodelling), the important role of inflammatory cytokine tumour necrosis factor alpha in regulating downstream repair responses, the role of chemotactic and mitogenic platelet-derived growth factor in the fibrogenic response, the involvement and roles of bone morphogenic protein and Wnt/B-catenin signalling pathways, as well as vascular endothelial growth factor-based angiogenesis during the osteogenic response. These new findings could potentially lead to identification of new targets for developing a future biological therapy. In addition, recent advances in cartilage tissue engineering highlight the promising potential for utilising multipotent mesenchymal stem cells (MSCs) for inducing regeneration of injured growth plate cartilage. This review aims to summarise current understanding of the mechanisms for growth plate injury repair and discuss some progress, potential and challenges of MSC-based therapies to induce growth plate cartilage regeneration in combination with chemotactic and chondrogenic growth factors and supporting scaffolds.

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B Houston, B H Thorp and D W Burt

ABSTRACT

Longitudinal bone growth occurs in the epiphyseal growth plate and is regulated by a network of paracrine and autocrine interactions. Bone morphogenetic proteins (BMPs) are a family of growth factors whose potent osteogenic properties suggest that they may play an important role within this network, but direct evidence for this is lacking. To address this question, a cDNA encoding chick BMP-7 was cloned from a chick embryo cDNA library. Sequence homology and evolutionary arguments strongly suggested that we had cloned the chicken BMP-7 homologue. Using a reverse transcription-PCR assay, BMP-7 expression was readily detected in bone, growth plate cartilage, brain and heart, and was just detectable in liver, skeletal muscle and adipose tissue. In contrast to the pattern of BMP-7 expression in the rat and mouse, no BMP-7 expression was detected in the chick kidney. In situ hybridization was used to locate the site of BMP-7 expression more precisely within the growth plate. BMP-7 expression was confined to hypertrophic chondrocytes adjacent to and at the tips of the metaphyseal vessels. No expression was detected in the reserve zone or in proliferating chondrocytes. These results point to a specific role for BMP-7 in the growth plate, possibly in osteoblast activation or as a chemotactic agent for the metaphyseal vessels.

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Shoshana Yakar, Haim Werner and Clifford J Rosen

The discovery of the growth hormone (GH)-mediated somatic factors (somatomedins), insulin-like growth factor (IGF)-I and -II, has elicited an enormous interest primarily among endocrinologists who study growth and metabolism. The advancement of molecular endocrinology over the past four decades enables investigators to re-examine and refine the established somatomedin hypothesis. Specifically, gene deletions, transgene overexpression or more recently, cell-specific gene-ablations, have enabled investigators to study the effects of the Igf1 and Igf2 genes in temporal and spatial manners. The GH/IGF axis, acting in an endocrine and autocrine/paracrine fashion, is the major axis controlling skeletal growth. Studies in rodents have clearly shown that IGFs regulate bone length of the appendicular skeleton evidenced by changes in chondrocytes of the proliferative and hypertrophic zones of the growth plate. IGFs affect radial bone growth and regulate cortical and trabecular bone properties via their effects on osteoblast, osteocyte and osteoclast function. Interactions of the IGFs with sex steroid hormones and the parathyroid hormone demonstrate the significance and complexity of the IGF axis in the skeleton. Finally, IGFs have been implicated in skeletal aging. Decreases in serum IGFs during aging have been correlated with reductions in bone mineral density and increased fracture risk. This review highlights many of the most relevant studies in the IGF research landscape, focusing in particular on IGFs effects on the skeleton.

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Yangli Xie, Siru Zhou, Hangang Chen, Xiaolan Du and Lin Chen

Skeletons are formed through two distinct developmental actions, intramembranous ossification and endochondral ossification. During embryonic development, most bone is formed by endochondral ossification. The growth plate is the developmental center for endochondral ossification. Multiple signaling pathways participate in the regulation of endochondral ossification. Fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling has been found to play a vital role in the development and maintenance of growth plates. Missense mutations in FGFs and FGFRs can cause multiple genetic skeletal diseases with disordered endochondral ossification. Clarifying the molecular mechanisms of FGFs/FGFRs signaling in skeletal development and genetic skeletal diseases will have implications for the development of therapies for FGF-signaling-related skeletal dysplasias and growth plate injuries. In this review, we summarize the recent advances in elucidating the role of FGFs/FGFRs signaling in growth plate development, genetic skeletal disorders, and the promising therapies for those genetic skeletal diseases resulting from FGFs/FGFRs dysfunction. Finally, we also examine the potential important research in this field in the future.

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OK Oz, R Millsaps, R Welch, J Birch and JE Zerwekh

Aromatase catalyzes the synthesis of estrogen from its androgen precursors. Estrogen is known to be important in regulating long bone growth and epiphyseal plate closure. To assess whether there may be growth plate-specific production of estrogen, we performed reverse transcriptase polymerase chain reaction (RT-PCR) to determine whether aromatase transcripts are present in the human growth plate. Immunohistochemistry was also employed to identify the specific sites of expression. Growth plates were obtained from an adolescent male and female undergoing ephysectomy to counter premature growth plate closure in the opposite leg. Aromatase transcripts were detected in RNA preparations from both growth plates. The aromatase protein was mainly expressed in the zone of maturation and the hypertrophic zone, with greatest expression in the latter. Since estrogen receptors are known to be expressed in chondrocytes, this data is consistent with a role for local estrogen production in the autocrine/paracrine control of long bone growth and growth plate maturation.

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Julian C Lui, Ola Nilsson and Jeffrey Baron

For most bones, elongation is driven primarily by chondrogenesis at the growth plates. This process results from chondrocyte proliferation, hypertrophy, and extracellular matrix secretion, and it is carefully orchestrated by complex networks of local paracrine factors and modulated by endocrine factors. We review here recent advances in the understanding of growth plate physiology. These advances include new approaches to study expression patterns of large numbers of genes in the growth plate, using microdissection followed by microarray. This approach has been combined with genome-wide association studies to provide insights into the regulation of the human growth plate. We also review recent studies elucidating the roles of bone morphogenetic proteins, fibroblast growth factors, C-type natriuretic peptide, and suppressor of cytokine signaling in the local regulation of growth plate chondrogenesis and longitudinal bone growth.

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R Rizzoli, JP Bonjour and SL Ferrari

Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue. At a given age, bone mass results from the amount of bone acquired during growth, i.e. the peak bone mass (Bonjour et al., 1991, Theintz et al. 1992) minus the age-related bone loss which particularly accelerates after menopause. The rate and magnitude of bone mass gain during the pubertal years and of bone loss in later life may markedly differ from one skeletal site to another, as well as from one individual to another. Bone mass gain is mainly related to increases in bone size, that is in bone external dimensions, with minimal changes in bone microarchitecture. In contrast, postmenopausal and age-related decreases in bone mass result from thinning of both cortices and trabeculae, from perforation and eventually disappearance of the latter, leading to significant alterations of the bone microarchitecture (Fig. 1).

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Patricia K Russell, Michele V Clarke, Jarrod P Skinner, Tammy P S Pang, Jeffrey D Zajac and Rachel A Davey

Androgens play a key role in skeletal growth and maintenance in males and can mediate their actions, at least in part, via the androgen receptor (AR) in osteoblasts. To investigate the mechanisms by which androgens exert their effects via the AR in mineralizing osteoblasts and osteocytes, we identified gene targets/pathways regulated by the AR using targeted gene expression and microarray approaches on bone isolated from mice in which the AR is specifically deleted in mineralizing osteoblasts and osteocytes (mOBL-ARKOs). Gene ontology mining indicated a number of biological processes to be affected in the bones of mOBL-ARKOs including skeletal and muscular system development and carbohydrate metabolism. All genes identified to have altered expression in the bones of mOBL-ARKOs were confirmed by Q-PCR for their androgen responsiveness in an androgen deprivation and replacement mouse model. The osteoblast genes Col1a1 and Bglap and the osteoclast genes Ctsk and RANKL (Tnfs11) were upregulated in the bones of mOBL-ARKOs, consistent with the increased matrix synthesis, mineralization, and bone resorption observed previously in these mice. Of significant interest, we identified genes involved in carbohydrate metabolism (adiponectin and Dpp4) and in growth and development (GH, Tgfb (Tgfb2), Wnt4) as potential targets of androgen action via the AR in mineralizing osteoblasts.

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Tadeusz Niedźwiedzki and Joanna Filipowska

Bone is a dynamic tissue that undergoes constant remodeling. The appropriate course of this process determines development and regeneration of the skeleton. Tight molecular control of bone remodeling is vital for the maintenance of appropriate physiology and microarchitecture of the bone, providing homeostasis, also at the systemic level. The process of remodeling is regulated by a rich innervation of the skeleton, being the source of various growth factors, neurotransmitters, and hormones regulating function of the bone. Although the course of bone remodeling at the cellular level is mainly associated with the activity of osteoclasts and osteoblasts, recently also osteocytes have gained a growing interest as the principal regulators of bone turnover. Osteocytes play a significant role in the regulation of osteogenesis, releasing sclerostin (SOST), an inhibitor of bone formation. The process of bone turnover, especially osteogenesis, is also modulated by extra-skeletal molecules. Proliferation and differentiation of osteoblasts are promoted by the brain-derived serotonin and hypothetically inhibited by its intestinal equivalent. The activity of SOST and serotonin is either directly or indirectly associated with the canonical Wnt/β-catenin signaling pathway, the main regulatory pathway of osteoblasts function. The impairment of bone remodeling may lead to many skeletal diseases, such as high bone mass syndrome or osteoporosis. In this paper, we review the most recent data on the cellular and molecular mechanisms of bone remodeling control, with particular emphasis on the role of osteocytes and the nervous system in this process.

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Kathryn L Auld, Stephen P Berasi, Yan Liu, Michael Cain, Ying Zhang, Christine Huard, Shoichi Fukayama, Jing Zhang, Sung Choe, Wenyan Zhong, Bheem M Bhat, Ramesh A Bhat, Eugene L Brown and Robert V Martinez

Based on its homology to the estrogen receptor and its roles in osteoblast and chondrocyte differentiation, the orphan nuclear receptor estrogen-related receptor α (ERRα (ESRRA)) is an intriguing therapeutic target for osteoporosis and other bone diseases. The objective of this study was to better characterize the molecular mechanisms by which ERRα modulates osteoblastogenesis. Experiments from multiple systems demonstrated that ERRα modulates Wnt signaling, a crucial pathway for proper regulation of bone development. This was validated using a Wnt-luciferase reporter, where ERRα showed co-activator-dependent (peroxisome proliferator-activated receptor gamma co-activator 1α, PGC-1α) stimulatory effects. Interestingly, knockdown of ERR α expression also enhanced WNT signaling. In combination, these data indicated that ERRα could serve to either activate or repress Wnt signaling depending on the presence or absence of its co-activator PGC-1α. The observed Wnt pathway modulation was cell intrinsic and did not alter β-catenin nuclear translocation but was dependent on DNA binding of ERRα. We also found that expression of active ERRα correlated with Wnt pathway effects on osteoblastic differentiation in two cell types, consistent with a role for ERRα in modulating the Wnt pathway. In conclusion, this work identifies ERRα, in conjunction with co-activators such as PGC-1α, as a new regulator of the Wnt-signaling pathway during osteoblast differentiation, through a cell-intrinsic mechanism not affecting β-catenin nuclear translocation.