Systemic and Local Regulation of the Growth Plate

Eerden, Bram C. J. van der; Karperien, Marcel; Wit, Jan M.

doi:10.1210/er.2002-0033

Cited by 486 publications

(373 citation statements)

References 288 publications

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“…Therefore, our results encourage the further study of rapamycin interaction with the Indian hedgehog (Ihh)/PTHrP feedback loop [27], so far not explored.…”

Section: Discussionmentioning

confidence: 55%

“…Beyond providing support for growth-plate chondrocytes, the extracellular matrix is involved in the control of growth factor diffusion [27] and is linked to cartilage mineralization. The matrix structure varies in transverse and longitudinal cartilage septa [28] and, worthy of note, matrix mineralization does occur in longitudinal septa of the lower hypertrophic zone, whereas transverse septa are rarely mineralized [29].…”

Section: Discussionmentioning

confidence: 99%

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Rapamycin retards growth and causes marked alterations in the growth plate of young rats

et al. 2007

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Rapamycin is a potent immunosuppressant with antitumoral properties widely used in the field of renal transplantation. To test the hypothesis that the antiproliferative and antiangiogenic activity of rapamycin interferes with the normal structure and function of growth plate and impairs longitudinal growth, 4-week-old male rats (n=10/ group) receiving 2 mg/kg per day of intraperitoneal rapamycin (RAPA) or vehicle (C) for 14 days were compared. Rapamycin markedly decreased bone longitudinal growth rate (94±3 vs. 182±3 μm/day), body weight gain (60.2±1.4 vs. 113.6±1.9 g), food intake (227.8±2.6 vs. 287.5±3.4 g), and food efficiency (0.26±0.00 vs. 0.40± 0.01 g/g). Signs of altered cartilage formation such as reduced chondrocyte proliferation (bromodeoxiuridine-labeled cells 32.9±1.4 vs. 45.2±1.1%), disturbed maturation and hypertrophy (height of terminal chondrocytes 26±0 vs. 29±0 μm), and decreased cartilage resorption (18.7±0.5 vs. 31.0±0.8 tartrate-resistant phosphatase alkaline reactive cells per 100 terminal chondrocytes), together with morphological evidence of altered vascular invasion, were seen in the growth plate of RAPA animals. This study indicates that rapamycin can severely impair body growth in fastgrowing rats and distort growth-plate structure and dynamics. These undesirable effects must be kept in mind when rapamycin is administered to children.

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“…Therefore, our results encourage the further study of rapamycin interaction with the Indian hedgehog (Ihh)/PTHrP feedback loop [27], so far not explored.…”

Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Rapamycin retards growth and causes marked alterations in the growth plate of young rats

et al. 2007

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“…(9) The two nuclear ERs, ERa and ERb, as well as the membrane Gprotein-coupled receptor GPR30 proposed to be an ER, are expressed in growth plate cartilage. (10)(11)(12)(13)(14)(15)(16) ERa is the main functional ER in the mouse growth plate, although ERb slightly modulates longitudinal bone growth in female but not in male mice. (17,18) We recently demonstrated that female GPR30 À/À mice displayed reduced longitudinal bone growth and reduced growth plate height that could not be reduced further by E2 treatment.…”

Section: J Jbmrmentioning

confidence: 99%

The role of estrogen receptor α in growth plate cartilage for longitudinal bone growth

Börjesson

Lagerquist

Liu

et al. 2010

Journal of Bone and Mineral Research

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Estrogens enhance skeletal growth during early sexual maturation, whereas high estradiol levels during late puberty result in growth plate fusion in humans. Although the growth plates do not fuse directly after sexual maturation in rodents, a reduction in growth plate height is seen by treatment with a high dose of estradiol. It is unknown whether the effects of estrogens on skeletal growth are mediated directly via estrogen receptors (ERs) in growth plate cartilage and/or indirectly via other mechanisms such as the growth hormone/ insulin-like growth factor 1 (GH/IGF-1) axis. To determine the role of ERa in growth plate cartilage for skeletal growth, we developed a mouse model with cartilage-specific inactivation of ERa. Although mice with total ERa inactivation displayed affected longitudinal bone growth associated with alterations in the GH/IGF-1 axis, the skeletal growth was normal during sexual maturation in mice with cartilagespecific ERa inactivation. High-dose estradiol treatment of adult mice reduced the growth plate height as a consequence of attenuated proliferation of growth plate chondrocytes in control mice but not in cartilage-specific ERa À/À mice. Adult cartilage-specific ERa À/À mice continued to grow after 4 months of age, whereas growth was limited in control mice, resulting in increased femur length in 1-year-old cartilage-specific ERa À/À mice compared with control mice. We conclude that during early sexual maturation, ERa in growth plate cartilage is not important for skeletal growth. In contrast, it is essential for high-dose estradiol to reduce the growth plate height in adult mice and for reduction of longitudinal bone growth in elderly mice. ß

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“…The inhibitory effects of GCs on growth are primarily mediated by disruption of chondrogenesis at the growth plate (8). This occurs via direct effects of GCs on chondrocyte growth and apoptosis (9,10), as well as through changes to factors such as those in the insulin-like growth factor (11) and vascular endothelial growth factor pathways (12), which disturb normal growth plate function.…”

mentioning

confidence: 99%

Sclerostin antibody treatment enhances bone strength but does not prevent growth retardation in young mice treated with dexamethasone

Marenzana¹,

Greenslade²,

Eddleston³

et al. 2011

Arthritis & Rheumatism

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Objective. Exposure to supraphysiologic levels of glucocorticoid drugs is known to have detrimental effects on bone formation and linear growth. Patients with sclerosteosis lack the bone regulatory protein sclerostin, have excessive bone formation, and are typically above average in height. This study was undertaken to characterize the effects of a monoclonal antibody to sclerostin (Scl-AbI) in mice exposed to dexamethasone (DEX).Methods. Young mice were concomitantly treated with DEX (or vehicle control) and Scl-AbI antibody (or isotype-matched control antibody [Ctrl-Ab]) in 2 independent studies. Linear growth, the volume and strength of the bones, and the levels of bone turnover markers were analyzed.Results. In DEX-treated mice, Scl-AbI had no significant effect on linear growth when compared to control treatment (Ctrl-Ab). However, in mice treated with DEX and Scl-ABI, a significant increase in trabecular bone at the femoral metaphysis (bone volume/total volume ؉117% versus Ctrl-Ab-treated mice) and in the width and volume of the cortical bone at the femoral diaphysis (؉24% and ؉20%, respectively, versus CtrlAb-treated mice) was noted. Scl-AbI treatment also improved mechanical strength (as assessed by 4-point bending studies) at the femoral diaphysis in DEXtreated mice (maximum load ؉60% and ultimate strength ؉47% in Scl-AbI-treated mice versus Ctrl-Abtreated mice). Elevated osteocalcin levels were not detected in DEX-treated mice that received Scl-AbI, although levels of type 5b tartrate-resistant acid phosphatase were significantly lower than those observed in mice receiving DEX and Ctrl-Ab.Conclusion. Scl-AbI treatment does not prevent the detrimental effects of DEX on linear growth, but the antibody does increase both cortical and trabecular bone and improves bone mechanical properties in DEX-treated mice.Glucocorticoid (GC)-based drugs have potent immunosuppressive and antiinflammatory properties and have assumed an important role in the treatment of many types of inflammatory and autoimmune conditions. However, drugs of this type are associated with a range of well-known side effects (1). One of the most serious problems associated with GC exposure is a deleterious effect on bone, which leads to a high proportion of patients who, after receiving long-term GC therapy, develop GC-induced osteoporosis and are susceptible to bone fractures (2). The detrimental effect of GCs on bone strength has been reported to involve many different mechanisms, including inhibition of osteoblastic bone formation, increased osteoclastic bone resorption, changes in calcium balance, and inhibition of the osteoanabolic action of sex steroids (3). More recently, it has also been proposed that GC exposure not only may cause changes to bone mass and bone architecture, but also may alter the localized material properties of bone (4).When administered to children or to growing

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Systemic and Local Regulation of the Growth Plate

Cited by 486 publications

References 288 publications

Rapamycin retards growth and causes marked alterations in the growth plate of young rats

Rapamycin retards growth and causes marked alterations in the growth plate of young rats

The role of estrogen receptor α in growth plate cartilage for longitudinal bone growth

Sclerostin antibody treatment enhances bone strength but does not prevent growth retardation in young mice treated with dexamethasone

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