RECENT RESEARCH ON THE GROWTH PLATE: Mechanisms for growth plate injury repair and potential cell-based therapies for regeneration

Abstract

Injuries to the growth plate cartilage often lead to bony repair, resulting in bone growth defects such as limb length discrepancy and angulation deformity in children. Currently utilised corrective surgeries are highly invasive and limited in their effectiveness, and there are no known biological therapies to induce cartilage regeneration and prevent the undesirable bony repair. In the last 2 decades, studies have investigated the cellular and molecular events that lead to bony repair at the injured growth plate including the identification of the four phases of injury repair responses (inflammatory, fibrogenic, osteogenic and remodelling), the important role of inflammatory cytokine tumour necrosis factor alpha in regulating downstream repair responses, the role of chemotactic and mitogenic platelet-derived growth factor in the fibrogenic response, the involvement and roles of bone morphogenic protein and Wnt/B-catenin signalling pathways, as well as vascular endothelial growth factor-based angiogenesis during the osteogenic response. These new findings could potentially lead to identification of new targets for developing a future biological therapy. In addition, recent advances in cartilage tissue engineering highlight the promising potential for utilising multipotent mesenchymal stem cells (MSCs) for inducing regeneration of injured growth plate cartilage. This review aims to summarise current understanding of the mechanisms for growth plate injury repair and discuss some progress, potential and challenges of MSC-based therapies to induce growth plate cartilage regeneration in combination with chemotactic and chondrogenic growth factors and supporting scaffolds.

Limb specific Acvr1‐knockout during embryogenesis in mice exhibits great toe malformation as seen in Fibrodysplasia Ossificans Progressiva (FOP)

“…This indicates that deregulation in early stages of development, due to a lack of Acvr1 expression, possibly cannot be compensated later. This is in accordance with studies showing that the height of the proliferative zone during endochondral ossification already determines the longitudinal growth potential of long bones . In another mouse model, which used a Col2‐specific KO of Acvr1 , limiting its deficiency to chondrocytes, it was observed that even though all five digits were developing, their ossification was delayed .…”

NPNT is Expressed by Osteoblasts and Mediates Angiogenesis via the Activation of Extracellular Signal-regulated Kinase

“…Furthermore, angiogenesis plays a crucial role during the healing process of bone fractures and growth plate injuries4142. Therefore, identifying new angiogenic factors may facilitate the development of new therapeutic treatments for skeletal pathologies and injuries.…”

Altered paracrine signaling from the injured knee joint impairs postnatal long bone growth

“…The GP likely becomes independent from the IPFP after ~P8 (due both to the intervening presence of the secondary ossification center as well as to cessation of Igf1 expression in the fat pad), which could also explain why it takes longer for bone growth to be significantly impaired when the injury is induced at P14 vs. P1. Finally, we cannot exclude the possibility that the IPFP and/or other local tissues hosting cells with osteochondrogenic potential, such as the synovium, bone marrow or the perichondrial groove of Ranvier (Hindle et al, 2017; Yang et al, 2013; Karlsson et al, 2009; Chung and Xian, 2014), can contribute to bone growth not only with paracrine signals, but also with progenitor cells (see for example Fig. S9 in [Yang et al, 2013]), such that cell death within these tissues in Pit::DTR mice depletes a pool of cells that participates in recovery of the injured bones.…”