The function of the resting zone is not well understood. Our findings suggest that the resting zone contains unipotent chondrocytic stem cells, capable of generating new columnar clones of proliferative chondrocytes. When the proliferative and and hypertrophic zones of the growth plate are experimentally removed, the resting zone is capable of regenerating the entire growth plate.
Determinants of growth plate polarity and spatial orientation
The growth plate shows spatial asymmetry or polarity. For example, proliferative chondrocytes undergo terminal differentation when they approach the metaphyseal but not the epiphyseal border of the growth plate. The adjacent bone, like the cartilage, also exhibits spatial polarity. Metaphyseal, but not epiphyseal, blood vessels and bone cells invade growth plate, remodeling the growing cartilage into bone. The signals that confer spatial polarity are not known. Our findings indicate that these signals arise within the cartilaginous growth plate and do not come from the adjacent bone tissue.
A second spatial property of growth plate cartilage involves the alignment of cell columns relative to the overall bone anatomy. When proliferative zone chondrocytes divide, daughter cells align themselves in a direction parallel to the long axis of the bone. As a result, cell clones are arranged in columns parallel to this axis. This orientation maintains growth along a defined axis and thus determines the overall shape of the bone. Our studies suggest that the spatial alignment of chondrocytes into columns is directed by a morphogen, produced by the resting zone cartilage that diffuses into the proliferative zone setting up a concentration grandient and that the proliferative chondrocytes then align themselves along that gradient. The chemical nature of this putative morphogen is under investigation.
The rate of longitudinal bone growth (and hence linear growth of the organism) falls progressively with age. In humans, fetal growth approaches 100 cm/year. At birth, the growth rate has decreased to 50 cm/year, and by mid-childhood, 5 cm/year. A similar progressive decline in bone growth occurs in other mammals. The differences among mammals in final skeletal size (e.g. between a mouse and an elephant) appears to be determined in part by the rapidity of this decline.
The decline in growth rate with increasing age is due largely to a decrease in the rate of growth plate chondrocyte proliferation. Growth plate transplantation experiments indicate that this decline in proliferation is not due to a hormonal or other systemic mechanism but rather to a mechanism intrinsic to the growth plate. We refer to this phenomenon as growth plate senescence.
Our findings suggest that growth plate senescence occurs because the stem-like cells in the resting zone of the growth plate have a finite proliferative potential. As the cells replicate, they gradually exhaust this potential, causing growth to slow and finally come to a halt. Thus, growth plate senescence appears not to be a function of time per se but rather of the cumulative number of divisions that the stem-like cells have undergone.
This concept, that growth plate senescence depends on cell replication, provides an explanation for the phenomenon of catch-up growth, the supranormal linear growth that occurs after release from growth-inhibiting conditions. This phenomenon was previously attributed to a central nervous system mechanism. However, the fact that growth inhibition also slows growth plate senescence suggests the following alternative explanation. The normal process of growth plate senescence depends on the cumulative number of replications that growth plate chondrocytes have undergone. Consequently, conditions that suppress growth plate chondrocyte proliferation conserve the proliferative capacity of the chondrocytes, thus slowing senescence. Therefore, following transient growth inhibition, growth plates retain a greater proliferative capacity, are less senescent, and hence show a greater growth rate than expected for age, resulting in catch-up growth. Our recent data suggest that this explanation applies also to human catch-up growth.
We are currently exploring the mechanisms that limit proliferation of these stem-like cells.
In some mammals, including humans, the growth plate is resorbed at the time of sexual maturation; the growth plate cartilage is replaced by bone. This process is termed epiphyseal fusion. Estrogen is pivotal for epiphyseal fusion in both young men and women. This key role for estrogen was confirmed recently with the recognition of two genetic disorders, estrogen deficiency due to mutations in the aromatase gene and estrogen resistance due to mutations in the estrogen receptor-alpha gene. In both of these conditions, the growth plate fails to fuse and growth persists, albeit slowly, into adulthood.
The mechanism by which estrogen promotes epiphyseal fusion is not well understood. We have recently found evidence that estrogen does not stimulate ossification of cartilage directly but instead accelerates the normal process of growth plate senescence, secondarily causing earlier fusion. In particular fusion appears to be triggered when the chondrocyte proliferation rate approaches zero. Estrogen, by accelerating senescence, hastens replicative senescence and thus causes earlier fusion.
We have worked to identify some of the key paracrine factors regulating endochondral bone formation in the growth plate. We have assembled evidence that fibroblast growth factors, retinoids, natriuretic peptides, and bone morphogenetic proteins serve as local signals to orchestrate this process.
Children with significant systemic illness often show poor skeletal growth. The mechanisms responsible for this growth inhibition may involve multiple circulating factors, including decreased IGF-I, increased glucocorticoid, decreased thyroid hormone, decreased nutrients and increased cytokines. Our research has focused on two aspects of this complicated issue, increased glucocorticoid and decreased nutritional intake.
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