Regulation of Long Bone Growth in Vertebrates; It Is Time to Catch Up

Abstract

The regulation of organ size is essential to human health and has fascinated biologists for centuries. Key to the growth process is the ability of most organs to integrate organ-extrinsic cues (eg, nutritional status, inflammatory processes) with organ-intrinsic information (eg, genetic programs, local signals) into a growth response that adapts to changing environmental conditions and ensures that the size of an organ is coordinated with the rest of the body. Paired organs such as the vertebrate limbs and the long bones within them are excellent models for studying this type of regulation because it is possible to manipulate one member of the pair and leave the other as an internal control. During development, growth plates at the end of each long bone produce a transient cartilage model that is progressively replaced by bone. Here, we review how proliferation and differentiation of cells within each growth plate are tightly controlled mainly by growth plate-intrinsic mechanisms that are additionally modulated by extrinsic signals. We also discuss the involvement of several signaling hubs in the integration and modulation of growth-related signals and how they could confer remarkable plasticity to the growth plate. Indeed, long bones have a significant ability for "catch-up growth" to attain normal size after a transient growth delay. We propose that the characterization of catch-up growth, in light of recent advances in physiology and cell biology, will provide long sought clues into the molecular mechanisms that underlie organ growth regulation. Importantly, catch-up growth early in life is commonly associated with metabolic disorders in adulthood, and this association is not completely understood. Further elucidation of the molecules and cellular interactions that influence organ size coordination should allow development of novel therapies for human growth disorders that are noninvasive and have minimal side effects.

Figure 1.

Allometric and isometric modes of growth. Drawings represent rhinoceros beetles (left) and spotted salamanders (right) at different stages of growth. The indicated length ratios between body parts are shown, normalized so that the value at the earliest stage is 1.

Figure 2.

Variation of bone–body proportions during human growth. The allometric-isometric switch is shown for two human leg segments. (Figure was plotted with data extracted from graphs in Ref. .)

Figure 3.

Autonomous and regulative organ growth. A, Response of autonomous (a) and regulative (b) organs to cell addition. B, Normal organ development (a) compared to different outcomes upon cell ablation, depending on whether the organ follows an autonomous program (b) or there is regulation based on the pool of progenitors (c) or on the size of the organ (d). (Figure was based on Ref. .)

Figure 4.

Control of organ size is mostly intrinsic but is subject to modulation in interspecies transplantation studies. When limb primordia are reciprocally grafted between salamander species differing in size, a mild extrinsic influence is observed (double-headed arrow). (Figure was redrawn from photographs in Ref. .) When limb primordia are reciprocally grafted between salamander species differing in size (double-headed arrow), a mild extrinsic influence is observed (*).

Figure 5.

Development and regulation of the long bones. A–D, Different stages of the endochondral ossification process. See main text for details. D, Summary of the local and systemic signals that regulate long bone growth and their interaction at the level of the growth plate. Dashed line represents that few examples are known. The inset represents the different parts of a growing bone.

Figure 6.

Integration and coordination of extracellular and intracellular growth cues. The funnel represents the network of interrelated signaling pathways that receives, integrates, and modulates all the cues that will ultimately affect cell growth, proliferation, and survival. The extracellular signals that are not collected by RTKs or GPCRs could still go through the two filters depicted (receptor and postreceptor level). Note that some signals will undergo several rounds of processing until they impact on cell growth, proliferation, or survival, either in the original cell or a neighbor. See end of Section III for further details

Figure 7.

CUG and progressive loss of growth potential in mammals. A, Idealized growth trajectories for normal and type A and B CUG. In type B, the growth trajectory is identical to that of normal growth, but delayed in time. B–D, Variation of tibial growth rate in postnatal development of the indicated species. [Figure was plotted using our unpublished data (B) or extracted from graphs in Ref. (C) and Ref. (D).]

Figure 8.

Differences between whole-body and local CUG. CUG after systemic GC treatment (A) and local GC infusion (B) differ in the associated bone growth rate during the recovery period. [Figure was plotted with data extracted from graphs in Ref. (A) and Ref. (B).]