Normal, regulated growth of skeletal bones is a critical part of mammalian development. This is a complex process that involves the growth of cartilage 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 develop from a variety of progenitor cells, over 60% of osteoblasts in mammals originate from a class called hypertrophic chondrocytes (HCs). HCs are versatile cells involved in a variety of bone development and maintenance tasks, including wound healing and normal blood vessel formation. However, the specific mechanisms behind how HCs perform these tasks are not known.
A group of researchers studied the roles of HCs in bone development in mice. Professor Liu Yang and Dr. Chao Zheng from the Fourth Military Medical University of 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 turn into bone tissue, the team looked at the new forms HCs take on at different stages of bone development. 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 a malformed backbone. Their long bones, like the femur, had fewer blood vessels.
[HC-ablated] The mice exhibited a dwarfism phenotype, reduced trabecular bone structure, and prolonged healing of puncture injuries, highlighting the essential role of HC lineage expansion in bone growth and repair.”
Liu Yang, Professor, Fourth Military Medical University
The team then studied the gene expression patterns of HCs to understand their transformation pathways. Eight pathways led to bone marrow formation. one led to bone formation. Within the bone formation pathway, the team found seven subtypes. Their expressive patterns suggest that:
- Three subtypes were associated with bone formation
- One subtype is involved in cartilage formation
- One subtype involves the layer of periosteum that surrounds the surface of the bone
- One subtype formed skeletal stem cells
- One subtype regulated the formation of new blood vessels within the bone. The team called these cells pre-angiogenic progenitors, or PADs
The team analyzed proteins secreted by the PADs to determine which ones triggered blood vessel formation. “We identified factors such as Vegfa, Thbs4, Fn1, Cxcl1, Col6a1 and Col1a2; secreted by PADs to signal endothelial cells. Dr. Zheng said, adding “Our further results indicated that PADs likely communicated with endothelial cells through the Thbs4-(Cd36/Cd47) path.“
Previous studies have shown that Thrombospondin 4, or Thbs4, is extremely potent at inducing blood vessel formation in many other tissues. The team found that Thbs4 supplementation increased blood vessel formation and healing in leg bones taken from HC-ablated mice.
Summarizing these findings, Professor Yang says, “Collectively, the present study demonstrates a critical role of HC progeny in bone growth and injury repair by secreting THBS4 to regulate angiogenesis. These findings also provided translational insights that could be exploited to enhance bone injury repair and treat defective angiogenesis.He adds that further research is needed to fully understand how PADs regulate blood vessel formation, including the roles of other signaling factors secreted by PADs.
Source:
Journal Reference:
Song, S., et al. (2025). Progeny of hypertrophic chondrocytes promote angiogenesis by secreting THBS4 during bone growth and injury repair. Bone research. DOI:10.1038/s41413-025-00469-2. https://www.nature.com/articles/s41413-025-00469-2.
