Читать книгу Recent Research in Nutrition and Growth - Группа авторов - Страница 18

Insight into plant growth saltation and stasis is well described. Evidence for on/off growth switches clarifies protein-mediated processes of inhibition and disinhibition at the cellular level. These include protein-mediated interactions that adjust cell growth and elongation patterns to the time of day and annual cycle. This occurs as environmental influences like light, temperature, and water activate and deactivate gene-based molecular interactions to promote or inhibit both stem elongation and flowering. In this way, phenotypic saltation and stasis growth of the plant arises from molecular-level gating complexes involving, for example, protein responses to light, which in turn alter the expression of circadian clock genes whose expression controls the time frame of cell elongation peaks [14].

While animals, including fish, rats, rabbits, and lambs, and humans have all been documented to grow by saltatory spurts [12], the molecular-level mechanisms underlying the timing and magnitude of these discrete growth events remain to be detailed. A measurable saltation is the expression of a biological process organizing stop/start events that integrate cell proliferation, hypertrophy, and functionality. The multiple start and stop control points involved in cell cycle progression form the fundamental cellular basis for saltation and stasis. Animal models identify episodic gene expression patterns and cyclic bursts of cell proliferation in regenerating zebra fish fins [15]. Limb elongation at the endochondral growth plate in mammalian animal models reflects an interplay among cell division, matrix synthesis, cellular hypertrophy, and cell shape changes with input from locally mediated regulatory systems [13, 16–19]. Control mechanisms for saltatory expression and inhibition have the opportunity to operate at each of these points.

It is likely that similar biological mechanisms underlie phenotypic growth spurts in humans, and growth saltations are a manifestation of cellular proliferation and expansion events that reflect a summary of genetic expression patterns in the context of environmental contingencies (Fig. 2a). Children grow to be small or tall through activities at the site of long-bone growth, the endochondral growth plate, the anatomical “action site” for length or height growth. Here, the abrupt saltatory bursts underlying long-bone elongation are achieved as the responsible cells, chondrocytes, experience their life cycle. A series of maturational stages characterized by changing cellular morphology and protein expression patterns leads to their final transition into hypertrophic cells, a coordinated event amongst chondrocyte cells that is the primary driver behind bone elongation [18]. Following proliferative and secretory phases, chondrocytes undergo as much as a 10- to 20-fold volume expansion, effectively providing a hydraulic elongation of the bone [13, 19]. Both the number of chondrocytic cells within this “hypertrophic zone” and the magnitude of their expansion determine bone elongation rates [16, 17].

Details of the life cycle of chondrocytes provide insights into how growth in length and height can be modulated. Each cellular developmental phase provides an opportunity for advancement or arrest of growth, contingent on signal integration in the growth plate microenvironment (Fig. 2b). In brief, each of the sequential stages in chondrocyte maturation has the potential to be a critical juncture, a decision point or gate, for progression to potential growth [20]. These critical points include chondrocyte emergence from mesenchymal stem cells (MSCs) (gate 1), the initiation of chondrocytic proliferation (gate 2), cell cycle arrest (gate 3), inhibition/disinhibition of hypertrophy (gate 4), and vascular invasion (gate 5) (Fig. 2b). At each of these points, environmental influences have the potential to alter the expression of stage-specific extracellular-matrix proteins and their associated chemical partners. These are time-specific interactions, which can either arrest the chondrocytic cascade or permit its progression. Ultimately determining the number of hypertrophic cells that are turned over into bone at the chondro-osseous junction, this system offers numerous interactional points whereby a genetic growth program can be enhanced or perturbed. The confluence of particular signals and signal concentrations, some of which reflect the body’s metabolic status, allows the cellular machinery of the growth plate to adjust progression based on time-specific appropriateness of bone growth. In this way, the timing of cell stage transitions and quiescence are monitored, and saltations are permitted to emerge from stasis intervals.

Fig. 2. a Body growth reflects the integrated expansion of bone, muscle, and fat as a functional unit. Length growth saltation timing or frequency (when and how often saltations occur) and amplitude (how much elongation/deposition occurs at a saltatory growth event) patterns reflect signals mediating systemic energy availability and cellular reserves that are both permissive and inhibitory. As environmental cues are transduced into intra- and intercellular signaling cascades, cellular life histories unfold as an expression of cross talk between cellular constituents, stage-specific secretion factors, and the microenvironment. b Saltatory growth in body length and height reflects bone elongation events driven by the volumetric expansion of hypertrophic chondrocytes at the endochondral growth plate (area in blue). After a series of life cycle maturational phases commencing with their earliest development in the so-called resting zone (RZ), chondrocytes enter a mitotic phase and become proliferative zone (PZ) cells. Thereafter, mitosis ceases and chondrocytes await signals permitting their volumetric expansion (becoming cells of the prehypertrophic zone, PHZ). Bone elongation occurs when these cells are released to expand, becoming hypertrophic zone (HZ) cells. Thereafter, mineralization of bone commences in the ossification zone (OZ). This sequence provides a series of 5 sequential critical gates whereby environmental regulatory cues can modulate cell cascade progression through chemical messenger promotion and inhibition. Integrated cellular expansion at the HZ results in saltatory bursts and determine growth rate and size at the full body level.

The chemical controls orchestrating cellular changes underlying growth saltations are many. These include morphogenic proteins, a class of intercellular signaling molecules that determine the pace of chondrocytic differentiation and progression by acting across concentration gradients. Indian hedgehog (Ihh) protein is a morphogen that regulates the most critical stage of the growth cascade, hypertrophy. Secreted by prehypertrophic chondrocytes, Ihh determines the pace of their advancement to hypertrophic swelling via a negative feedback loop involving parathyroid-related protein [21]. As the growth plate extracellular matrix becomes compliant for cellular volume expansion, Ihh secretion is decreased, and cellular hypertrophy is permitted. A driving factor behind this cellular transition is the expression of specific matrix proteins, which in turn are influenced by the integration of global and local energy signals. In these steps, Ihh concomitantly shapes both growth potential and the specific timing of a growth event.