scholarly journals Evolution and future of growth plate therapeutics

2021 ◽  
Author(s):  
David B. Allen ◽  
Nadia Merchant ◽  
Bradley S. Miller ◽  
Philippe F. Backeljauw
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Linear Growth ◽  
Therapeutic Potential ◽  
Skeletal Growth ◽  
Local Regulation ◽  
Factor I ◽  
The Past ◽  
Growth Promoting ◽  
Regulation Of Growth

Abstract Background: Longitudinal bone growth is regulated by multiple endocrine signals (e.g. growth hormone, insulin-like growth factor I, estrogen, androgen) and local factors (e.g. fibroblast growth factors and their receptors and the C-natriuretic peptide/NPR-2 pathway). Summary: Abnormalities in both endocrine and local regulation of growth plate physiology cause many disorders of human skeletal growth. Knowledge of these pathways creates therapeutic potential for sustaining or even augmenting linear growth. Key message: During the past four decades, advances in understanding growth plate physiology have been accompanied by development and implementation of growth-promoting treatments that have progressed in both efficacy and specificity of action. This paper reviews the history and continuing evolution of growth plate therapeutics.

Effects of testosterone on skeletal growth in lambs as assessed by labeling index of chondrocytes in the metacarpal bone growth plate

1994 ◽  
Vol 72 (10) ◽  
pp. 2629-2634 ◽  
Author(s):  
José M. Peralta ◽  
Andrew M. Arnold ◽  
W. Bruce Currie ◽  
Michael L. Thonney
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Metacarpal Bone ◽  
Skeletal Growth ◽  
Labeling Index

scholarly journals Amino-Terminal Propeptide of C-Type Natriuretic Peptide and Linear Growth in Children: Effects of Puberty, Testosterone, and Growth Hormone

2007 ◽  
Vol 92 (11) ◽  
pp. 4294-4298 ◽  
Author(s):  
Robert C. Olney ◽  
Timothy C. R. Prickett ◽  
Timothy G. Yandle ◽  
Eric A. Espiner ◽  
Joan C. Han ◽  
...  
Keyword(s):  
Short Stature ◽  
Growth Plate ◽  
Natriuretic Peptide ◽  
Linear Growth ◽  
Gh Deficiency ◽  
Gh Treatment ◽  
Amino Terminal ◽  
Pubertal Growth ◽  
Potential Biomarker ◽  
Growth Promoting

Abstract Context: C-type natriuretic peptide (CNP), a paracrine factor of the growth plate, plays a key role in stimulating bone growth. The amino-terminal propeptide of CNP (NTproCNP) is produced in equimolar amounts with CNP and is measurable in plasma, providing a potential biomarker for growth plate activity and, hence, linear growth. Objective: We explored the effects of puberty, testosterone, and GH treatment on NTproCNP levels in normal and short-statured children. Design: This was a retrospective analysis of samples obtained during previous studies. Setting: The study was conducted at a pediatric clinical research center. Subjects: Children with short stature due to GH deficiency, idiopathic short stature (ISS), or constitutional delay of growth and maturation (CDGM) were studied (n = 37). A cohort of normal-statured adolescent boys was also studied (n = 23). Interventions: Children with GH deficiency and ISS were studied before and during testosterone and/or GH treatment. Boys with CDGM and healthy controls were studied once. Main Outcome Measures: The main outcomes were NTproCNP levels before and during growth-promoting therapy and during pubertal growth. Results: Children with short stature due to GH deficiency, ISS, or CDGM had comparable baseline levels of NTproCNP, and levels increased markedly in response to GH or testosterone treatment. In boys with CDGM, levels were comparable with height-matched controls but were less than those from age-matched controls. In healthy boys, NTproCNP appears to peak with the pubertal growth spurt. Conclusions: NTproCNP levels increase during growth-promoting therapy and are increased during puberty in boys. This novel biomarker of growth may have clinical utility in the evaluation of children with short stature and for monitoring growth-promoting therapy.

Growth-promoting properties of the internal milieu of pregnant and lactating rats

1990 ◽  
Vol 258 (1) ◽  
pp. E98-E102
Author(s):  
M. Chiang ◽  
S. M. Russell ◽  
C. S. Nicoll
Keyword(s):  
Serum Insulin ◽  
Tail Length ◽  
Skeletal Growth ◽  
Internal Environment ◽  
Kidney Capsule ◽  
Rat Embryos ◽  
Factor I ◽  
Internal Milieu ◽  
Igf I ◽  
Growth Promoting

The growth-promoting properties of the internal milieu of pregnant and lactating rats were investigated using transplanted whole rat embryos or fetal paws. When placed under the kidney capsule of intact nonpregnant hosts and incubated for 12 days, such transplants grow rapidly, and tissues differentiate normally. Thus they provide an accurate means of assessing the growth-promoting properties of the internal environment of host animals in different physiological states. Transplant growth during days 0-11 of pregnancy was similar to that observed in age-matched virgin control hosts during an equivalent 12-day period. However, growth of transplants was decreased by 40% in hosts during days 10-22 of pregnancy and by approximately 30% in hosts during days 1-13 or days 11-23 of lactation. Increase in tail length, which was used as an index of maternal skeletal growth, was reduced by 50% during the second half of pregnancy and the early and late periods of lactation compared with age-matched virgin females. No such inhibition was recorded during the first half of pregnancy. Compared with virgins, serum insulin-like growth factor I (IGF-I) levels were reduced by approximately 20% on days 6 and 10 of pregnancy, and by 63-66% during the second half of gestation. Serum IGF-I levels rose during lactation to reach prepregnancy levels by day 12, but a second decline occurred by day 18 postpartum.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Circulating C-Type Natriuretic Peptide (CNP) Rescues Chondrodysplastic CNP Knockout Mice from Their Impaired Skeletal Growth and Early Death

Endocrinology ◽  
2010 ◽  
Vol 151 (9) ◽  
pp. 4381-4388 ◽  
Author(s):  
Toshihito Fujii ◽  
Yasato Komatsu ◽  
Akihiro Yasoda ◽  
Eri Kondo ◽  
Tetsuro Yoshioka ◽  
...  
Keyword(s):  
Body Weight ◽  
Natriuretic Peptide ◽  
Knockout Mice ◽  
Bone Growth ◽  
Therapeutic Potential ◽  
Body Weight Gain ◽  
Early Death ◽  
Systemic Administration ◽  
Skeletal Growth ◽  
Endochondral Bone

C-type natriuretic peptide (CNP) is a potent stimulator of endochondral bone growth through a subtype of membranous guanylyl cyclase receptor, GC-B. Although its two cognate natriuretic peptides, ANP and BNP, are cardiac hormones produced from heart, CNP is thought to act as an autocrine/paracrine regulator. To elucidate whether systemic administration of CNP would be a novel medical treatment for chondrodysplasias, for which no drug therapy has yet been developed, we investigated the effect of circulating CNP by using the CNP transgenic mice with an increased circulating CNP under the control of human serum amyloid P component promoter (SAP-Nppc-Tg mice). SAP-Nppc-Tg mice developed prominent overgrowth of bones formed through endochondral ossification. In organ culture experiments, the growth of tibial explants of SAP-Nppc-Tg mice was not changed from that of their wild-type littermates, exhibiting that the stimulatory effect on endochondral bone growth observed in SAP-Nppc-Tg mice is humoral. Then we crossed chondrodysplastic CNP-depleted mice with SAP-Nppc-Tg mice. Impaired endochondral bone growth in CNP knockout mice were considerably and significantly recovered by increased circulating CNP, followed by the improvement in not only their longitudinal growth but also their body weight. In addition, the mortality of CNP knockout mice was greatly decreased by circulating CNP. Systemic administration of CNP might have therapeutic potential against not only impaired skeletal growth but also other aspects of impaired growth including impaired body weight gain in patients suffering from chondrodysplasias and might resultantly protect them from their early death.

scholarly journals Growth, growth factors and diabetes

2004 ◽  
pp. U109-U117 ◽  
Author(s):  
F Chiarelli ◽  
C Giannini ◽  
A Mohn
Keyword(s):  
Bone Growth ◽  
Linear Growth ◽  
Final Height ◽  
Pubertal Development ◽  
Normal Growth ◽  
Diabetic Patients ◽  
Hormonal Changes ◽  
The Past ◽  
Igf I

Type 1 diabetes mellitus (T1DM) and other chronic diseases in children are well known to adversely affect linear growth and pubertal development. In the years immediately following the introduction of insulin therapy, short stature was consistently reported in children with T1DM. However, over the past 50 years significant improvement in the prognosis for growth and final height in children with diabetes has been achieved. Although pre-pubertal and post-pubertal growth are important phases in growth, puberty and its related hormonal changes represent a critical phase for growth gain and final height particularly in patients with T1DM. Growth impairment reported in diabetic patients is dependent on abnormalities in physiological bone growth and corresponds to abnormalities of the growth hormone-insulin-like growth-I (GH-IGF-I) axis. These alterations seem to be related to appropriate insulin levels and thereby to glycaemic control as judged by haemoglobin levels. Modern diabetes care, particularly intensified insulin regimens, might improve metabolic control in patients with T1DM, therefore preventing abnormalities of the GH-IGF-I axis and leading to normal growth and final height similar to that of their unaffected peers.

The effects of systemic insulin, insulin-like growth factor-I and growth hormone on bone growth and turnover in spontaneously diabetic BB rats

1992 ◽  
Vol 134 (3) ◽  
pp. 485-492 ◽  
Author(s):  
J. Verhaeghe ◽  
A. M. H. Suiker ◽  
W. J. Visser ◽  
E. Van Herck ◽  
R. Van Bree ◽  
...  
Keyword(s):  
Weight Gain ◽  
Growth Factor ◽  
Bone Formation ◽  
Bone Growth ◽  
Diabetic Rats ◽  
Skeletal Growth ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Bb Rats ◽  
Igf I

ABSTRACT Spontaneously diabetic BB rats have a markedly depressed longitudinal bone growth and bone formation/turnover. In this study, male diabetic BB rats were infused intraperitoneally or subcutaneously for 2 weeks with hormones that are believed to stimulate skeletal growth and/or trabecular bone formation: insulin (3 or 4 U/day), human GH (hGH; 400 mU/day), recombinant human insulin-like growth factor-I (rhIGF-I; 300 or 600 μg/day) and testosterone (80 μg/100 g body weight per day). Saline-treated diabetic BB rats had decreased plasma concentrations of IGF-I and osteocalcin (OC) (OC, 3·7 ±0·3 vs 13·1 ± 0·8 (s.e.m.) nmol/l in controls); bone histomorphometry showed decreased epiphyseal width, osteoblast surface (0·04±0·04 vs 1·5±0·3%) and osteoid surface, and mineral apposition rate (MAR) (1·8±0·5 vs 7·9±0·6 μm/day). Testosterone and hGH infusions had no effect on weight loss or on decreased skeletal growth and bone formation of diabetic rats, nor did they increase plasma IGF-I concentrations. Insulin infusions into diabetic rats resulted in hyperinsulinaemia and accelerated weight gain. The epiphyseal width, osteoblast/osteoid surfaces and OC levels of insulin-treated rats were normalized or stimulated well above control values (osteoblast surface, 4·3 ±0·8%; plasma OC, 16·1 ± 1·4 nmol/l); the MAR (4·0 ± 0·9 μm/day) was only partly corrected after the 2-week infusion. Infusions of rhIGF-I into diabetic rats doubled but did not restore plasma IGF-I levels to normal; weight gain, however, was similar to that in control rats. IGF-I treatment had no effect on epiphyseal width, osteoblast/osteoid surfaces and OC concentrations, but improved the decreased MAR (4·6±1·2 μm/day). These results indicate (1) that the decreased epiphyseal width and osteoblast recruitment of diabetic BB rats are directly related to their insulin deficiency, and (2) that IGF-I, administered systemically, corrects, in part, the decreased MAR in diabetes, suggesting a role in osteoblast function and/or mineralization. Journal of Endocrinology (1992) 134, 485–492

scholarly journals Limb- and tendon-specific Adamtsl2 deletion identifies a soft tissue mechanism modulating bone length

2018 ◽  
Author(s):  
Dirk Hubmacher ◽  
Stetson Thacker ◽  
Sheila M. Adams ◽  
David E. Birk ◽  
Ronen Schweitzer ◽  
...  
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Soft Tissues ◽  
Skeletal Growth ◽  
Suitable Model ◽  
Functional Link ◽  
Fibrillin 1 ◽  
Cell Layers ◽  
Severe Short Stature

AbstractDisproportionate distal limb shortening is the hallmark of acromelic dysplasias. Among them, geleophysic dysplasia is a rare, frequently lethal condition characterized by severe short stature, musculoskeletal, cardiac, pulmonary, and skin anomalies. Geleophysic dysplasia results from dominant fibrillin-1 (FBN1) or recessive ADAMTSL2 mutations, suggesting a functional link between ADAMTSL2 and FBN1. Mice lacking ADAMTSL2 die at birth, precluding analysis of postnatal skeletal growth and mechanisms underlying the skeletal anomalies of geleophysic dysplasia. We show that Adamtsl2 is expressed in limb soft tissues, predominantly in tendon. Expression in developing bones is limited to their terminal cell layers that are destined to become articular cartilage and is absent in growth plate cartilage. Adamtsl2 conditional deletion in limb mesenchyme using Prxl-Cre led to an acromelic dysplasia, providing a suitable model for investigation of geleophysic dysplasia. Unexpectedly, conditional Adamtsl2 deletion using Scx-Cre, a tendon-specific deleter, also impaired skeletal growth. Specific morphogenetic anomalies were seen in Achilles tendon, along with FBN1 accumulation. Thus, ADAMTSL2, shown here to bind fibrillin microfibrils in vitro, limits fibrillin microfibril formation in tendons and promotes tendon growth. The findings suggest that reduced bone growth in geleophysic dysplasia results from external tethering by short tendons rather than intrinsic growth plate anomalies.

scholarly journals Spatial distribution of growth hormone receptor, insulin-like growth factor-I receptor and apoptotic chondrocytes during growth plate development

2005 ◽  
Vol 184 (3) ◽  
pp. 543-553 ◽  
Author(s):  
J Cruickshank ◽  
D I Grossman ◽  
R K Peng ◽  
T R Famula ◽  
A M Oberbauer
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Growth Plate ◽  
Bone Growth ◽  
Resting Cells ◽  
Apoptotic Cells ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

Linear bone growth depends upon proliferation, maturation, and apoptosis of growth plate chondrocytes, processes regulated by growth hormone (GH) and insulin-like growth factor-I (IGF-I). To investigate the contribution of GH, IGF-I and apoptosis to growth plate function, the expression of GH receptor (GHR) and IGF-I receptor (IGF-IR) mRNA were evaluated by in situ hybridization in fractionated costochondral growth plates of growing rats (at 2, 4, and 7 weeks). Apoptosis was determined by TUNEL assay and morphology in histological sections. GHR mRNA was greatest in resting cells with hypertropic cells increasing GHR expression with increasing age. Hypertropic and resting cell IGF-IR mRNA declined over the ages studied. Receptor mRNA expression was altered by exposing cells to GH or IGF-I. GH and IGF significantly decreased GHR mRNA in proliferative cells. GH and IGF also decreased IGF-IR mRNA in resting cells and the 2- and 4-week-old proliferative and hypertropic cells. Treating cells in culture with GH increased the number of apoptotic cells across all ages and zones. Histologically, apoptotic cells were observed at the chondro-osseous junction and within actively proliferating chondrocytes but not in resting cells. Apoptosis was highest at 4 weeks of age with lateral regions displaying the greatest number of cells undergoing apoptosis. These data indicate that apoptosis plays a role in growth plate function, particularly spatial configuration as indicated by the preferential lateral cell apoptosis. The susceptibility of proliferative cells to GHR and IGF-IR down regulation during the period of greatest apoptosis supports a role for the GH–IGF axis in both proliferation and apoptosis during growth plate development.

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