1. Introduction

2. Physiological Process of Longitudinal Growth

2.2. Bone Structure

Bone formation begins in utero in the six or seven weeks of age and started as a cartilage model template [6]. This cartilage ossifies at the diaphyseal side and grows on the epiphyseal side. In the late teens or early twenties, a person reaches skeletal maturity [7]. By then, all the cartilage has been replaced by bone, so no further growth in bone length is possible. This mechanism is highly regulated and requires continuous signal interchange between cartilage and bone cells (Figure 1).

Bone is a metabolically active organ that provides structural support, facilitates movement, and protects vital organs. It is also an endocrine organ that plays an important role in regulating mineral and acid-base homeostasis and in blood cell production (hematopoiesis). Therefore, although bones are hard structures, they continually replenish themselves and regenerate, consistently making new bone. In fact, the human skeleton is replaced every 7-10 years [9]. During childhood, that process allows bones to growth in length and change the shape. This process requires the interaction of 3 types of cells: osteoclasts, osteocytes and osteoblasts. There is also a 4th type of cell (Figure 1) that are the osteoprogenitor population.

Osteoblasts: Bone Forming Cells [10]. They are cuboidal cells that are located along the bone surface comprising 4–6% of the total and are largely known for their bone forming function [11]. They arise from a common plenipotentiary multipotent stromal cell (MSC). The synthesis of bone matrix by osteoblasts occurs in two main steps: deposition of organic matrix and its subsequent mineralization.

Osteocytes: Mature Bone Cells. They are the most numerous cells in the bone, representing 90–95% of the total amount, as well as the most long-lived with a life span of up to 25 years. Osteocytes are spider-shaped cells buried in the mineralized bone matrix, descended from MSC lineage through osteoblast differentiation [12]. Each osteocyte has up to 50 long and 450 branched cellular processes that extend along the bone within a network of interconnected canaliculi. These facilitate the cell-cell communication trough inter-cellular transport signaling molecules, such as prostaglandins and nitric oxide. This network is essential in coordinating the response of bone to mechanical and biological signals. Through mechanical transduction processes, osteocytes can transduce extracellular signals to elicit cellular responses to regulate bone formation and resorption.

Osteoclasts: Bone Resorbing Cells. They are terminally differentiated multinucleated cells originate from mononuclear cells of the hematopoietic stem cell lineage. They are polarized cells that breaks down bone and cartilage tissue. This function is critical in growth, maintenance, repair, and remodeling of bones.

Osteoprogenitors: They are stem cells located in the bone that play a prodigal role in bone repair and growth. These cells developed from MSC, and they are the precursors to the more specialized bone cells (osteocytes and osteoblasts). They reside in the bone marrow, and they reduce with age. Dysfunction of osteoprogenitor cells may delay ossification and lead to a spectrum of diseases such as dwarfism and Kashin-Beck disease [13].

The architecture performs its essential mechanical functions (Figure 4). Bone is covered by an external surface called periosteum that consists of two layers: an outer fibrous layer and an inner more cellular and vascular layer that can form bone. The cortical bone or compact bone is the dense outer surface of bone that forms a protective layer around the internal cavity. It is located in the diaphysis, and it has double blood supply that allows loss of one source of circulation without adversely affecting the viability of the tissue. Cortical bone forms the external layer of all bones but is found principally in the diaphysis of long bones. Cortical bone is made up of osteons, osteocytes are present within the osseous tissue surrounded by an extracellular matrix composed of calcium and phosphorous-rich hydroxyapatite. Collagen fibers present within the extracellular matrix provide limited flexibility to cortical bone. Trabecular or cancellous bone is present in the extreme of long bones or metaphysis. It is porous and trabeculated tissue and its spatial complexity contributes the maximal strength with minimum mass. The epiphysis is the enlarged end of the long bones produced by trabecular bone. Any disorganization of this net structure implicates not only bone deformities but also a smaller amount of adaptation to stress forces and more chances to bone fractures [14].

Figure 4. Structure and components of long bone. Long bones consisting of a long shaft (the diaphysis) plus two articular (joint) surfaces, called epiphyses. They are comprised mostly of compact bone, but they also contain spongy or trabecular bone and marrow in the hollow center (the medullary cavity). The diagram shows the main structural features of bone as well as a magnified view showing some of the finer detail of trabecular (A) cortical bone (B) and growth plate (C). Created with BioRender.com.

Figure 4. Structure and components of long bone. Long bones consisting of a long shaft (the diaphysis) plus two articular (joint) surfaces, called epiphyses. They are comprised mostly of compact bone, but they also contain spongy or trabecular bone and marrow in the hollow center (the medullary cavity). The diagram shows the main structural features of bone as well as a magnified view showing some of the finer detail of trabecular (A) cortical bone (B) and growth plate (C). Created with BioRender.com.

2.4. Skeleton Development and Growth Rely on the Coordinated Interaction of Cartilage and Bone Cells

Development and growth of the skeleton occur through the coordinated interaction of cartilage and bone cells. HC in the GP are the greatest contributors to lengthening of the cartilage template, therefore better understanding of how hypertrophic chondrocyte interacts with bone tissue will be critical to comprehend growth defects.

During bone growth, changes in both the cartilage and the bone compartments occurs, and for that, exist a close interaction between chondrocytes an osteoblast cells lineage. The idea that chondrocytes and bone cells talk to each other in the GP exists for decades [22]. However, until recently there has been little functional evidence that chondrocytes can directly control the differentiation and activity of either osteoclasts or osteoblasts. Nowadays we know that cell enlargement is not the only important function of hypertrophic chondrocytes. In vivo and ex vivo studies has shown that small molecules can transit between these tissues. In fact, several studies pointed out that osteocytes produce cytokines, as receptor activator of nuclear factor kappa-β ligand (RANKl), essential for the osteoclast differentiation and function and survival in mature bone [23,24,25]. Now we also know that the whole joint is involved in the development of articular cartilage (AC). In particular, the interaction (crosstalk) between cartilage and subchondral bone is a central feature for osteoarthritis (OA) progression.

To understand the crosstalk between cartilage and bone cells, it is necessary to know the GP development. Both AC and the GP arise in part from the embryonic growth zone and are regulated by the axis involving Indian Hedgehog and Parathyroid hormone related protein (IHH-PTHrP) [26]. The proliferative chondrocytes express PTHrP and colonize both the forming articular cartilage and GP structures. Once the secondary ossification center (SOC) is formed, PTHrP is detected in the resting zone of the GP and in the superficial region of the AC. It is believed that PTHrP and its receptor retards chondrocyte hypertrophy preventing their mineralization. In the other size, Ihh produced by prehypertrophic chondrocytes has an opposite function, and blocks proliferation promoting final differentiation and hypertrophy.

After birth and during normal growth, the epiphyseal plate will expand in length by continuous cell division of chondrocytes in the proliferative zone, which is accompanied by further secretion of extracellular matrix. Then chondrocytes in the hypertrophic zone begin to increase in size (hypertrophy), stop secreting collagen and other proteoglycans, and begin secreting alkaline phosphatase, an enzyme essential for mineral deposition. Final step is the replacement of hypertrophic cartilage by bone. This requires vascular invasion, a step initiated and controlled by the interaction of angiogenic and anti-angiogenic factors [27,28]. Hypertrophic chondrocytes attract blood vessels into the center of the cartilage template, leading to the formation of a highly vascularized endosteum within the nascent marrow space, stimulated primarily by the secretion of vascular endothelial growth factor (VEFG)[29].

Osteoblasts, accompanying vascular invasion, lay down endochondral bone to replace cartilage. Bone tissue formation takes place through a series of phases, osteoblast proliferation, followed by extracellular matrix maturation and matrix mineralization [30]. A range of transcription factors are known to be involved in the regulation of osteogenesis but two of the most broadly studied are Runt-related transcription factor 2 (Runx2) and Osterix (Osx) [31,32]. Runx2 is considered the major transcription factor controlling osteoblast commitment and differentiation. Runx2 expression is upregulated in several murine OA models, suggesting a role in disease pathogenesis [33]. In fact, overexpression of Runx2 can induce osteogenesis in vitro and in vivo, demonstrated by increased osteoblastic markers, Osteopontin and Osteocalcin [34,35]. Contrary, Runx2 null mice show a complete absence of ossification, owing to the maturational arrest of osteoblasts [36]. Osx is another important transcription factor, since Osx-deficient mice show an absence of osteoblasts and defective bone formation [37]. Other transcription factors of interest in relation to osteogenesis are the distal less gene family. Overexpression of Dlx5 can accelerate osteoblast differentiation in vitro. Osteocytes derive from osteoblasts, being essentially osteoblasts surrounded by the products they have previously secreted. Osteocytes surrounded by matrix have an extensive canalicular network connecting them to each other and to bone surface (Figure1).

Sclerostin is another regulator factor controlling osteocyte differentiation. The loss of sclerostin, derived from the inactivation of the SOST gene, leads to sclerosteosis, a skeletal disorder characterized by high bone mass due to increased osteoblast activity. Several studies have suggested that sclerostin may be an osteocyte-derived factor that is transported to osteoblasts at the bone surface and inhibits bone formation [38,39]. Osteoclasts are multinucleated cells that resorb the bone matrix and degrade the cartilage during the endochondral ossification. They arise from the monocyte-macrophage lineage present in the hematopoietic marrow, under the stimulation of two pivotal cytokines: macrophage-colony stimulating factor (M-CSF) and RANKL, both mainly produced by osteoblasts [35] (Figure 1). Osteoblasts also produce osteoprotegerin (OPG) that acts as a decoy receptor for RANKL, inhibiting its binding to RANK expressed and negative regulation osteoclast maturation [40]. Studies have established those HC also express RANKL/OPG and support osteoclast formation [40,41]. Osteoclasts break down the newly formed bone to open up the medullary cavity and trabecular formation.

For years, we thought that death is the ultimate fate of terminally differentiated HCs. However, now we know that HC can become into osteoblasts and contribute to the full osteogenic lineage [38]. Chondrocytes transdifferentiate into osteoblasts that make new bone matrix during development [39]. This process occurs in a region it is known as “the transition zone or ossification zone” that is located adjacent to the hypertrophic zone. HC located in the transition have two fates. Some of them die, while others re-enter the cell cycle, switch off the chondrogenic program, activate the molecular program associated with pluripotency, and with osteogenesis, and they become osteoblasts able to synthesize new bone matrix. Support comes from imaging, morphological, and ultrastructural studies in vivo as well as linear tracing studies. Yang et al. [30] genetically labeled either hypertrophic chondrocytes (HC) by Col10a1-Cre or chondrocytes by tamoxifen-induced Agc1-CreERT2 using Enhanced green fluorescent protein (EGFP), LacZ or Tomato expression. Both Cre drivers were specifically active in chondrocytic cells and not in perichondrium, in periosteum or in any of the osteoblast lineage cells. After labeling, these cells were distributed throughout trabeculae surfaces and, in the endosteum, embedded within the bone matrix. In vitro studies demonstrated that a proportion of the non-chondrocytic cells derived from chondrocytes labeled by Col10a1-Cre or by Agc1-CreERT2 were functional osteoblasts [42]. HC can also instruct adjacent perichondrial cells to differentiate into osteoblasts [43]. Cell chondrocyte transdifferentiation has also been described in the literature in multiple times. Rat chondrocytes have been shown, when stimulated by Fibroblastic growth factor 23 (FGF-23), Neurobasal-A, epidermal growth factor (EGF), and insulin-like growth factor-1 (IGF-1) they can transdifferentiate into stellate neuronal cells [44]. Another example is what happens in atherosclerotic lesions. It was described in mice that they presented what seems to be the transdifferentiation of vascular smooth muscle to chondrogenic tissue via increased expression of tissue non-specific alkaline phosphatase and bone morphogenetic protein (BMP-2) activation [45]. Beyond these examples is important to know that transdifferentiation is not limited to artificial cell culture settings, or to a pathology but is also a natural phenomenon.

Besides transdifferentiation into bone-forming cells, HC induce bone formation at their adjacent regions by secreting matrix proteins, including type X collagen, and critical paracrine factors. As previously described, HC secrete VEGF that induce invasion of blood vessels from the perichondrium, and IHH hat regulate proliferation and differentiation and directs perichondrial cells to become osteoblasts. In addition, IHH acts further on periarticular chondrocytes at the end of the cartilage and therefore promotes the production of parathyroid hormone–related peptide (PTHrP)[46]. PTHrP acts opposite as Ihh and delays the chondrocyte differentiation into hypertrophic chondrocytes. These series of interactions establish the PTHrP-Ihh feedback loop that is essential to maintaining the GP structure and AC health (Figure 3). Actually, deletion of either the PTHrP gene or the PTH/PTHrP receptor gene leads to acceleration of differentiation of GP chondrocytes, bones exhibit a striking increase in osteoblast number and matrix accumulation and a reduction of vascular invasion [47,48]. Wnt signaling also plays an important role, studies have shown that misexpression of Wnt-4 accelerates the nonhypertrophic to hypertrophic transition and results in slightly advanced ossification [49]. Matrix metalloproteinase (MMP13) is expressed by hypertrophic chondrocytes and osteoblasts. We demonstrate that MMP13 is required for proper resorption of hypertrophic cartilage. Another pathway that has been recently implicated in the communication between cartilage and other bone cells is the epidermal growth factor receptor (EGFR) pathway. EGFR on chondrocytes activates the induction of matrix metalloproteinases (MMPs) as well as RANKL (Figure 4).

Figure 4. Molecular expression of the main factors involved in the dynamics of the postnatal growth plate. Colored bars mean that the protein is expressing in that region. If the bar does not have color and is only with oblique stripes, means that it is that it is not expressed in that area, but it is where it performs its function. When the bar has color and stripes means that it is expressed there, and the cell also has receptors for the protein.

Figure 4. Molecular expression of the main factors involved in the dynamics of the postnatal growth plate. Colored bars mean that the protein is expressing in that region. If the bar does not have color and is only with oblique stripes, means that it is that it is not expressed in that area, but it is where it performs its function. When the bar has color and stripes means that it is expressed there, and the cell also has receptors for the protein.

In this process, α-parvin, an integrin-associated focal adhesion protein, plays a significant role, regulating α-parvin the rotation of chondrocytes, which is an essential process for chondrocytes to form a columnar structure. The loss of this protein in animal models increases binucleation, raises cell death, and causes dilation of the resting zones of mature GP. Single-cell RNA-seq analyses revealed alterations in the transcriptome in all three zones (i.e., resting, proliferative, and hypertrophic zones) of the GP [50]. In conclusion, HC can recruit osteoclasts and osteoblasts to sites of cartilage remodeling. Thus, they can be considered as master regulators of endochondral bone formation.

In the other hand, articular cartilage, molecular crosstalk between chondrocytes and osteoblasts/osteocytes are likely of primary importance during bone growth. Osteocytes form an interconnected network throughout the cortical and trabecular bone, and these cells act as mechanosensory. Cytokine-sized and larger molecules can traverse between bone and cartilage in either healthy or diseased joints. These molecules are able to traverse osteocyte canaliculi, and this transport is increased by bone loading [51,52]. During the osteoarthritic process marked alterations in the composition of the cartilage matrix occurs, resulting in swelling of the matrix, and increased metabolic activity of chondrocytes and inducing hypertrophy and apoptosis. Production of matrix modifying factors such as MMPs by chondrocytes induce the response of load-sensing osteocytes. IGF-1 is an important factor in GP development, it is transported into cartilage mainly from osteocytes into the circulation. This transport occurs partly by diffusion across a concentration gradient but, in addition, mechanical loading has been shown to enhance the transport and promote growth [50]. Osteocytes also secrete FGF-23. FGF-23 suppressed chondrocyte proliferation and maturation via Indian hedgehog. FGF-23 is well established to play crucial roles in X-linked hypophophatemia (XLH) and growth retardation [53], actually inhibition of FGF23 partially rescued XLH phenotype [54] promoting growth. Inhibiting FGF-23 sems to be a crucial factor in OA disorders however this phenomenon is not completely explored.

GH interacts with growth plate through GH receptors (GHRs) located in chondrocytes and, indirectly, through systemic and local stimulation of IGF-1. Upon binding to GHR at the growth plate’s chondrocytes, it induces dimerization of the receptor, resulting in tyrosine phosphorylation of Janus-associated kinase 2 (JAK2), a tyrosine kinase associated with the intracellular domain of the receptor. Phosphorylation induces the kinase activity of JAK2, which in turn phosphorylates/activates a group of molecules known as signal transducers and activators of transcription (STATs). Upon activation, the STATs dimerize and translocate to the nucleus, where they regulate the expression of target genes responsible for GH action, including IGF-1 [55].

3. Defects in Interaction Lead to Growth Disorders

4. What We Already Know about Clinical Conditions That Associate Growth Retardation

5. Conclusions and Future Directions

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