Normal, regulated growth of skeletal bones is a crucial part of the growth of mammals. This is a complex process involving the growth of cartilaginous cells or chondrocytes, their transformation into bone-building cells or osteoblasts, and the formation of new blood vessels to supply the newly formed bone tissue. While osteoblasts evolve from a variety of progenitor cells, over 60% of osteoblasts in mammals originate from one class called hypertrophic chondrocytes (HYCs). HYCs are versatile cells involved in a variety of bone growth and maintenance tasks, including healing injuries and normal blood vessel formation. However, the specific mechanisms behind how HYCs carry out these tasks are not known.
A team of researchers has studied the roles HCs play in bone growth in mice. Professor Liu Yang and Dr. Chao Zheng from the Fourth Military Medical University, China, led this research effort. Having previously studied how HYCs can transform into bone tissue, the team looked at the new forms HYCs take through various stages of bone growth. First, the team created transgenic mice with the selective deletion of HYCs. Compared to normal mice, these HYC-ablated mice were smaller, with shorter limbs, rounded skulls and malformed backbones. Their long bones, like the femur, had fewer blood vessels. Next, the team studied the gene expression patterns of HYCs to understand their transformational pathways.
Eight pathways led to bone marrow formation; one led to bone formation. Within the second, the team found seven subtypes. Their expression patterns suggested that:
- Three subtypes were related to bone formation
- One subtype was involved in cartilage formation
- One subtype was involved in the periosteum layer that surrounds the bone surface
- One subtype formed skeletal stem cells
- One subtype regulated the formation of new blood vessels inside the bone. The team called these cells pro-angiogenic descendants or PADs
The team analyzed proteins secreted by PADs to identify which ones induced blood vessel formation. They thus pinpointed factors like VEGF-A, thrombospondin 4 (Thbs4), fibronectin (Fn1), two types of collagen (Col6a1 and Col1a2) and a chemokine (CXCL1) secreted by PADs to signal endothelial cells; further experiments led to speculate that PADs likely communicated with endothelial cells through the Thbs4 (Cd36/Cd47) pathway. In vitro assays, researchers documented the proangiogenic activity of THBS4 by promoting adhesion, migration and proliferation of vascular endothelia. Mechanistically, with Integrin α2 and GABA receptor α2δ1 being its receptors, THBS4 mediates angiogenesis in response to TGF-β1 using the PI3K/AKT pathway in endothelial cells.
Previous studies have shown that Thrombospondin 4 is highly potent at inducing blood vessel formation in many other tissues. The team found that supplementing Thbs4 increased blood vessel formation and healing in foot bones taken from HYC-ablated mice. Overall, there are enough dato to deem that there is a critical role of HYC descendants in bone growth and injury repair by THBS4 secretion to regulate angiogenesis. It has been well established indeed that osteogenesis is coupled with angiogenesis. Researches have indicated that proteinases like MMP13 and growth factors such as VEGF released by terminal HYCs were crucial for the ingrowth of blood vessels into HYC matrix.
These findings also shed translational insights that could be leveraged to enhance bone injury repair of bone and treat defective angiogenesis.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
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