α-parvin controls chondrocyte column formation and regulates long bone development

Abstract

Endochondral ossification requires proper control of chondrocyte proliferation, differentiation, survival, and organization. Here we show that knockout of α-parvin, an integrin-associated focal adhesion protein, from murine limbs causes defects in endochondral ossification and dwarfism. The mutant long bones were shorter but wider, and the growth plates became disorganized, especially in the proliferative zone. With two-photon time-lapse imaging of bone explant culture, we provide direct evidence showing that α-parvin regulates chondrocyte rotation, a process essential for chondrocytes to form columnar structure. Furthermore, loss of α-parvin increased binucleation, elevated cell death, and caused dilation of the resting zones of mature growth plates. Single-cell RNA-seq analyses revealed alterations of transcriptome in all three zones (i.e., resting, proliferative, and hypertrophic zones) of the growth plates. Our results demonstrate a crucial role of α-parvin in long bone development and shed light on the cellular mechanism through which α-parvin regulates the longitudinal growth of long bones.

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Funding

Lombardi and Shinozuka Experimental Pathology Research Endowment Fund, University of Pittsburgh

InnoHK@Health, Theme-based Research Scheme (Tl3-602/21-N) Guangdong High-level Hospital Construction Project (KJ012019517) Guangdong Provincial People’s Hospital Foundation (KY012021405) Guangdong-Dongguan Joint Research Scheme Guangdong-Hong Kong-Macau Program (2021B1515130004)

Natural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation)(2017B030301018)

National Natural Science Foundation of China (National Science Foundation of China)(82273308)

The Shenzhen Innovation Committee of Science and Technology, JCYJ20220530112817040, ZDSYS20220606101604009. the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen E010122002.