Evolution and future of growth plate therapeutics

“Longitudinal bone growth is regulated by multiple endocrine signals (e.g. growth hormone, insulinlike growth factor I, estrogen, androgen) and local factors (e.g. fibroblast growth factors and their receptors and the C-natriuretic peptide/NPR-2 pathway).”

“The resting zone chondrocytes, farthest from the primary ossification center, replicate at a slow rate and act as stem-like cells that replenish the pool of proliferative chondrocytes{if we can reintroduce these resting zone chondrocytes we may be able to reopen the growth plate}. Resting zone chondrocytes produce a ‘growth plate-orienting factor’ that instructs the proper spatial orientation of adjacent proliferative chondrocytes. As cells within the resting zone divide, the proliferative zone is formed in which chondrocytes replicate at a high rate, become arranged into columns, and contribute to bone elongation. Hypertrophic chondrocytes generated from terminal differentiation of proliferating zone chondrocytes enlarge in columns parallel to the axis of elongation. Cell swelling during chondrocyte hypertrophy enables chondrocytes within the growth plate to enlarge rapidly. This phase of endochondral ossification, during which chondrocytes increase their height about 6- to 10-fold, serves as the major factor regulating the growth rate amongst endochondral bones. Hypertrophic chondrocytes calcify surrounding extracellular matrix and produce factors that attract bone cell precursors, bone cells and blood vessel growth, and undergo apoptosis shortly before the blood vessels invade the chondrocyte lacuna. The overall effect of this process of chondrocyte proliferation, hypertrophy, and extracellular matrix secretion is elongation of bones and progressive creation of new bone tissue at the bottom of the growth plate. With age, the rate of longitudinal bone growth declines, caused primarily by a decrease in chondrocyte proliferation associated with other hormone-independent structural, functional, and molecular changes termed growth plate senescence. Evidence suggests that growth plate senescence occurs because the progenitor chondrocytes in the resting zone have a limited replicative capacity – gradually exhausted with increasing cell division{things like estrogen and FGFR3 may contribute to reducing the replicative capacity}.  When the proliferative capacity of stem-like cells in the resting zone is exhausted, and in the presence of sex hormones, growth plate cartilage becomes completely replaced by bone, an event termed epiphyseal fusion”

” According to the dual-effector hypothesis, GH promotes recruitment of resting chondrocytes into a proliferative state and stimulates local production of IGF-I, which then acts in a paracrine/autocrine fashion to increase chondrogenesis. The IGF-I signaling pathway plays an important role in promoting complete hypertrophic chondrocyte formation. These effects are predominantly due to growth plate-generated IGF-I, and IGF-I deficiency results in pre- and post-natal growth retardation marked in the growth plate by disorganized columnar chondrocytes, decreased cell proliferation and cell hypertrophy, increased apoptosis, and delayed vascular invasion. ”

“Estrogen influences longitudinal growth primarily and indirectly by augmenting GH secretion during puberty, but also through both growth-enhancing and -attenuating direct actions on the growth plate. A direct effect of estrogen is to advance growth plate senescence causing proliferative exhaustion, and thus epiphyseal fusion. An important mediator of this growth plate closure process is vascular endothelial growth factor (VEGF), the production of which is stimulated by estrogen in both males and females. Androgens stimulate linear growth partly due to aromatization to estrogens within growth plate cartilage, but also by direct interaction with androgen receptors on growth plate chondrocytes – explaining the GH- and IGF-I-independent growth stimulating effects of non-aromatizable compounds such as dihydrotestosterone and oxandrolone. Linear growth is slowed by deficiency of and accelerated by excess thyroid hormone. Hypothyroidism indirectly impedes linear growth by diminishing GH secretion and IGF-I, but also by decreasing chondrocyte proliferation and hypertrophy, slowing of vascular/bone cell invasion, and disruption of column organization. Glucocorticoid (GC) excess slows longitudinal bone growth by inhibiting chondrocyte proliferation, hypertrophy, and cartilage matrix synthesis. Diminished GH secretion and/or altered IGF-I bioavailability have been described in some GCtreated patients. Slowing of growth plate senescence due to GC appears to explain the phenomenon of catch-up growth following transient GC exposure and hypothyroidism.”

“Members of the FGF family of receptors (FGFRs) and their ligands are required for proper chondrocyte function, endochondral ossification and overall skeletal development. Proliferative chondrocytes express FGFR3 and prehypertrophic/hypertrophic chondrocytes express FGFR1. These pathways inhibit the proliferation of chondrocytes, thereby limiting the longitudinal growth of bones. Thus, activating mutations in FGFRs impede linear growth and cause skeletal phenotypes such as achondroplasia and hypochondroplasia. Accelerated linear growth and epiphyseal growth plate maturation in obese children, even in the setting of decreased GH production may be due to effects of increased insulin concentrations and activation of the insulin receptor in the growth plate. Leptin, increased in obese children, has direct effects on skeletal growth centers, enhancing chondrocyte proliferation and subsequent cell differentiation. Leptin also increases growth plate aromatase activity{this may explain why some obese children are taller than normal and others are shorter based on differential responses to estrogen} which along with estrogen produced through adipose tissue aromatization, accelerates skeletal maturation. Parathyroid hormone-related protein (PTHrP) supports chondrocytes and maintains the width of the growth plate. Mutations affecting PTHrP action (e.g. Gs-alpha) can result in a shortening of the proliferating zone, accelerated differentiation of hypertrophic chondrocytes, premature closure of the growth plate, and short stature. Vitamin D facilitates normal linear growth indirectly by increasing intestinal calcium and phosphate absorption, but vitamin D metabolites produced locally in the growth plate also decrease the proliferation of chondrocytes through the PTHrP pathway. Thus, the full effect of vitamin D on the growth plate physiology is incompletely understood.”

The paper some options for treatment for increasing growth plate based growth.  I recommend reading the whole paper.  I highlighted some stuff here because it does a great job explaining the mechanics of growth plate based height increase.