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The skeleton is an essential part of the human body that supports and facilitates body movement. Most of the bones are formed through a mechanism called endochondral ossification, which involves the formation of a cartilage template that will eventually be replaced by bone. Cartilage on the bone surface, however, will remain as articular cartilage in the joint. As abnormal cartilage formation leads to abnormal bone formation and various skeletal conditions, it is critical to understand cartilage development.
Cartilage development begins during embryogenesis. While bones have various shapes and sizes, the long bone (such as the femur, the tibia and metatarsal bones) is most commonly studied, since it constitutes half of the height. A critical stage of long bone growth is the postnatal period, during which most of the bone growth takes place. However, how cartilage develops after birth is still largely unclear. It is known that the growth hormone plays an important role in skeletal growth. However, children with growth hormone deficiency may not exhibit retarded growth until they are one to two years old. This is consistent with the data in mice, where the first ten days of growth is in fact growth hormone-independent. What then, controls skeletal growth in this early postnatal period?
Tomoya Uchimura, a CMDB PhD candidate working in the laboratory of Li Zeng, is investigating the role of Insulin-like growth factor II (IGF-II) on cartilage development during postnatal bone growth utilizing Igf-2 null mutant mice. He has performed detailed study on why IGF-II deficient bones are shorter and thinner. In long bone growth, cartilage cells go through a series of developmental process with defined stages of chondrocyte proliferation and hypertrophy, forming a zone of cartilage growth, the growth plate (GP). Tomoya has discovered that IGF-II is required for the correct timing of chondrocytes to advance through these stages. In addition, IGF-II is required for the formation of a secondary ossification center (SOC) that occurs at the end of the long bone, a unique phenomenon that only occurs in postnatal bone. Very interestingly, Igf-2 mutant does not just exhibit a simply delay, as WT and mutant bones of the same length differ significantly in cartilage structure. Furthermore, Tomoya delved into the mechanism of IGF-II-controlled cartilage gene expression and found that it promotes cartilage matrix gene expression and chondrocyte hypertrophy. This study sheds light on the critical growth-hormone independent neonatal period of skeletal growth, and provides insights into the understanding of human conditions such as Russell-Silver syndrome and the Beckwith-Wiedemann syndrome (BWS), where changes in stature are associated with altered IGF-II levels.
In addition to studying the role of IGF-II on normal cartilage development, Tomoya has also been also characterizing the function of IGF-II in resisting inflammatory cytokine-induced cartilage damage during development and in maintaining articular cartilage matrix and joint integrity in adults. These investigations represent this first thorough study on the role of IGF-II in postnatal bone and cartilage, and may lead to novel treatment methods for joint diseases such as osteoarthritis.