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 (HCs). HCs 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 HCs 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. The team's findings were published in Volume 13 of the journal Bone Research on November 10, 2025.
Having previously studied how HCs can transform into bone tissue, the team looked at the new forms HCs take through various stages of bone growth. First, the team created transgenic mice with the selective deletion of HCs. Compared to normal mice, these HC-ablated mice were smaller, with shorter limbs, rounded skulls and malformed backbones. Their long bones, like the femur, had fewer blood vessels.
"[HC-ablated] mice displayed a dwarfism phenotype, impaired trabecular bone structure, and prolonged healing of drill-hole injuries, underscoring an essential role of HC lineage extension in bone development and repair," remarked Prof. Yang.
Next, the team studied the gene expression patterns of HCs to understand their transformational pathways. Eight pathways led to bone marrow formation; one led to bone formation. Within the bone formation pathway, 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. "We pinpointed factors such as Vegfa, Thbs4, Fn1, Cxcl1, Col6a1, and Col1a2, secreted by PADs to signal endothelial cells," said Dr. Zheng, adding "Our further results indicated that PADs likely communicated with endothelial cells through the Thbs4-(Cd36/Cd47) pathway."
Previous studies have shown that Thrombospondin 4 or Thbs4 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 HC-ablated mice.
Summarizing these findings, Prof. Yang says, "Collectively, the present study demonstrates a critical role of HC descendants in bone growth and injury repair by secreting THBS4 to regulate angiogenesis. These findings also shed translational insights that could be leveraged to enhance bone injury repair of bone and treat defective angiogenesis." She adds that further research is needed to fully understand how PADs regulate blood vessel formation, including the roles of other signaling factors that PADs secrete.
