Growth Plate

Chondrocytes within the growth plate are organized in a precise pattern reflecting cell functionality. Randomly distributed stem cell chondrocytes lie adjacent to the epiphysis in a region termed the resting zone. Resting zone cells induced to divide produce columns of clo-nally expanding cells, forming the proliferative zone. The proliferative zone chondrocytes then mature in their metabolic activities, secrete additional matrix, and hypertrophy. This expansive proliferation and hypertrophy occurring in both growth plates essentially pushes the ends of the bone apart, resulting in overall elongation. The retention of cartilaginous growth plates permits elongation of bone by an internal mechanism, enabling structural support and maintenance of the physical configuration of the bone necessary for tendon and ligament insertion sites. In contrast to the endochondral growth process, intra-membranous bone enlarges by appositional deposition of osteoid matrix.

Fig. 1 Endochondral ossification stages. (Reprinted from Fig. 3.39, 37th edition of Gray's Anatomy, 1989, with permission from Elsevier.)


The osteoblast, the primary bone-forming cell, secretes type I collagen and proteoglycans to form a nonmineral-ized matrix that serves as scaffolding for hydroxyapatite crystal deposition by osteoblasts.1-3-1 The osteoblast requires a surface to lay down the osteoid. As the osteoblast becomes surrounded by mineralized matrix, it changes phenotype by losing much of its protein production organelles and forming protoplasmic processes that connect via gap junctions to the adjacent protoplasmic processes of other encased osteoblasts.1-4-1 Once surrounded by matrix, the cell is designated an osteocyte. The bulk of the osteocyte occupies a space within the bone known as the lacuna, while the protoplasmic processes occupy spaces termed canaliculi.[3] The protoplasmic process connections between osteocytes allow cellular communication, which becomes important during times of increased mechanical stress and hormonal control of serum calcium levels. In contrast to the osteoblast and osteocyte found in areas of active bone formation, bone-lining cells are present only on bone surfaces not actively forming bone. Bone-lining cells are reserve cells that differentiate into osteoblasts when needed, as during fracture repair, to actively create bone.[3] The osteoclast is the major bone resorbing cell. The osteoclast secretes acid hydrolases to dissolve the hydroxyapatite and enzymes to dissolve the protein scaffolding within bone.[5] The osteoclast maintains a polarity with only the side in contact with bone forming a ruffled membrane (Fig. 2). This ruffled edge localizes acids and enzymes permitting bone resorption within discrete sites.


Bone undergoes growth in two ways. Growth in the longitudinal plane of long bones is achieved through the process of chondrocyte activity within growth plates (endochondral ossification). Widening of long bones and increased size of flat bones is achieved through a process of cell division and subsequent ossification in all directions (appositional growth).[4] Within long bones, appositional growth occurs at the periosteum accompanied by resorption at the endosteum in order for the cortical bone width at the diaphysis to maintain mechanical stability.[4] During the process of endochondral ossification, chondrocytes proliferate, hypertrophy, and mineralize. The mineralized cartilage cores produced at the metaphysis of the bone are resorbed by osteoclasts and used as scaffolding on which osteoblasts can begin building bone. As the bone lengthens, mechanical forces applied by gravity and surrounding musculature force the bone to reshape itself by resorbing the outer edges of the

Fig. 2 Activation and communication between the osteoclast and the osteoblast: the BMU.

E2 Glucocorticoid

E2 Glucocorticoid

Fig. 3 Hormonal cascades involved in growth plate pro liferation.

which signals the osteoclast (Fig. 2). The unique relationship between these two cell types is known as the BMU (basic multicellular unit).[10] The major calcium regulating hormones are parathyroid hormone (PTH) and calcitonin, with T3, E2, and cytokines contributing to calcium homeostasis.[6-9,11,12] Low serum calcium levels stimulate PTH release that, along with T3, acts to promote the release of the IL-1 and IL-6 cytokines from osteoblasts. These cytokines stimulate bone resorption by the osteoclast leading to calcium release into the fluid surrounding the osteoclast, which is transported into the circulation to replenish serum calcium levels. In contrast, E2 inhibits osteoclast resorption by impairing osteoblastic release of these cytokines. The other major calcium regulator, calcitonin, is released in response to high serum calcium levels. Calcitonin acts directly on the osteoclast to inhibit its resorbing capabilities and promote bone formation through enhancing osteoblast proliferation.1-13-1

metaphysis. This process ensures that the bone retains the greatest mechanical stability in the face of normal wear and tear.[4]

The process of growth plate chondrocyte proliferation, hypertrophy, and mineralization is finely controlled through hormones that act both systemically and locally. These hormones include growth hormone (GH), insulinlike growth factor-I (IGF-I), thyroid hormone (T3), estrogen (E2), testosterone, vitamin D (Vit D3), and glucocorticoids (GCs);[6-9] the major effectors are GH and IGF-I. Growth hormone acts directly on chondrocytes to induce cell division in the resting zone and stimulates local IGF-I production by the proliferating and hypertrophic cells (Fig. 3). Growth hormone also stimulates systemic IGF-I production by the liver. Both local and systemic IGF-I promote proliferation and hypertrophy of cells within the growth plate. Estrogen (E2) directly drives chondrocyte proliferation and influences the growth plate by increasing GH release from the pituitary. Conversely, GCs inhibit GH release by the pituitary. Testosterone appears to promote growth plate closure by terminating chondrocyte proliferation after puberty.[8] Likewise, T3 acts directly on the chondrocytes to stop proliferation, although T3 stimulates the pituitary to release GH and promotes IGF-I release from the liver.


One primary function of bone is to serve as a calcium storage depot. The resorption of bone for the purpose of replenishing serum calcium levels is hormonally orchestrated. Much of the process is regulated by the osteoblast,


Bone constantly undergoes a process, termed remodeling. Bone is continuously resorbed by osteoclasts and replaced by osteoblasts daily. Much of the remodeling process is regulated by the osteoblast signaling the osteoclast (Fig. 2) to create the BMU.[14] The process initiates when bone experiences mechanical stress that generates microdamage. This mechanical stress ultimately determines the shape and morphology of the bone. Alterations in normal mechanical stress are sensed within the fluid of the canaliculi-connecting osteocytes. This activates the osteo-cytes to signal surrounding osteoblasts to recruit osteoclasts to the area. The osteoclasts bore through existing bone to the region requiring reinforcement, and together the osteoblast and osteoclast of the BMU repair and reinforce the stressed bone until it is mechanically sound. Remodeling periodically replaces old bone and microcracks, thus maintaining the overall structural integrity of the bone.


Mature skeletal size is determined by bone elongation. Bone length can be enhanced and accelerated by genetic selection for growth rate alterations or hormonal manipulation that also affect muscle deposition. Bone length must be balanced with maintaining bone strength. Disturbances in bone strength lead to undesirable consequences for human and animal health including excessive bone breakage. Overall, the skeleton is one of the most dynamic physiological systems. The constant, simultaneous, precise control over bone formation, degradation, growth, and required mineral regulation is imperative to the maintenance of healthy animals.

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