Roles of Local Soluble Factors in Maintaining the Growth Plate: An Update

Abstract

The growth plate is a cartilaginous tissue found at the ends of growing long bones, which contributes to the lengthening of bones during development. This unique structure contains at least three distinctive layers, including resting, proliferative, and hypertrophic chondrocyte zones, maintained by a complex regulatory network. Due to its soft tissue nature, the growth plate is the most susceptible tissue of the growing skeleton to injury in childhood. Although most growth plate damage in fractures can heal, some damage can result in growth arrest or disorder, impairing leg length and resulting in deformity. In this review, we re-visit previously established knowledge about the regulatory network that maintains the growth plate and integrate current research displaying the most recent progress. Next, we highlight local secretary factors, such as Wnt, Indian hedgehog (Ihh), and parathyroid hormone-related peptide (PTHrP), and dissect their roles and interactions in maintaining cell function and phenotype in different zones. Lastly, we discuss future research topics that can further our understanding of this unique tissue. Given the unmet need to engineer the growth plate, we also discuss the potential of creating particular patterns of soluble factors and generating them in vitro.

Molecular mechanisms of long bone growth and chondrocyte regulation: A narrative review

“…Bone morphogenetic proteins (BMPs), which belong to TGF-β superfamily, are involved in most processes related to skeletal development and play critical roles in cartilage formation and maintenance [36]. BMP2, BMP4, and BMP7 contribute to chondrocyte differentiation by regulating SOX9 expression, and promote endochondral ossification by regulating RUNX2 transcription [37][38][39].…”

“…This, in turn, activates the Gli gene family. Subsequently, Gli proteins enter the nucleus to control downstream gene expression, including SOX9, RUNX2, and parathyroid hormone-related protein (PTHrP) [36]. A negative feedback loop of Ihh and PTHrP maintains chondrocyte proliferation and differentiation [44,45].…”

“…Fibroblast growth factor (FGF) stimulates mitosis and angiogenesis. FGF activates the intracellular tyrosine kinase domain of the FGF receptor (FGFR), which subsequently acti-vates downstream signaling pathways such as including RAS-MAPK and phosphoinositide 3-kinase (PI3K)-AKT, that are essential for cell proliferation, differentiation, and survival [36,43]. Several studies have demonstrated that FGF2, FGF9, and FGF18 enhance mesenchymal stem cell differentiation, chondrocyte proliferation, and extracellular matrix synthesis [57][58][59].…”