Kindlin-2 deletion in osteoprogenitors causes severe chondrodysplasia and low-turnover osteopenia in mice

Background: Our recent studies demonstrate that the focal adhesion protein Kindlin-2 exerts crucial functions in the mesenchymal stem cells, mature osteoblasts and osteocytes in control of early skeletal development and bone homeostasis in mice. However, whether Kindlin-2 plays a role in osteoprogen...

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Autores principales:	Xiaohao Wu, Minghao Qu, Weiyuan Gong, Chunlei Zhou, Yumei Lai, Guozhi Xiao
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	Kindlin-2 Osteoprogenitor Skeletogenesis Chondrodysplasia Low-turnover osteopenia Diseases of the musculoskeletal system RC925-935
Acceso en línea:	https://doaj.org/article/fbc0cfc1cd364b4abc6632951716dc92
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spelling	oai:doaj.org-article:fbc0cfc1cd364b4abc6632951716dc922021-12-02T05:01:34ZKindlin-2 deletion in osteoprogenitors causes severe chondrodysplasia and low-turnover osteopenia in mice2214-031X10.1016/j.jot.2021.08.005https://doaj.org/article/fbc0cfc1cd364b4abc6632951716dc922022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2214031X2100067Xhttps://doaj.org/toc/2214-031XBackground: Our recent studies demonstrate that the focal adhesion protein Kindlin-2 exerts crucial functions in the mesenchymal stem cells, mature osteoblasts and osteocytes in control of early skeletal development and bone homeostasis in mice. However, whether Kindlin-2 plays a role in osteoprogenitors remains unclear. Materials and methods: Mice lacking Kindlin-2 expression in osterix (Osx)-expressing cells (i.e., osteoprogenitors) were generated. Micro-computerized tomography (μCT) analyses, histology, bone histomorphometry and immunohistochemistry were performed to determine the effects of Kindlin-2 deletion on skeletal development and bone mass accrual and homeostasis. Bone marrow stromal cells (BMSCs) from mutant mice (Kindlin-2fl/fl; OsxCre) and control littermates were isolated and determined for their osteoblastic differentiation capacity. Results: Kindlin-2 was highly expressed in osteoprogenitors during endochondral ossification. Deleting Kindlin-2 expression in osteoprogenitors impaired both intramembranous and endochondral ossifications. Mutant mice displayed multiple severe skeletal abnormalities, including unmineralized fontanel, limb shortening and growth retardation. Deletion of Kindlin-2 in osteoprogenitors impaired the growth plate development and largely delayed formation of the secondary ossification center in the long bones. Furthermore, adult mutant mice displayed a severe low-turnover osteopenia with a dramatic decrease in bone formation which exceeded that in bone resorption. Primary BMSCs isolated from mutant mice exhibited decreased osteoblastic differentiation capacity. Conclusions: Our study demonstrates an essential role of Kinlind-2 expression in osteoprogenitors in regulating skeletogenesis and bone mass accrual and homeostasis in mice. The translational potential of this article: This study reveals that Kindlin-2 through its expression in osteoprogenitor cells controls chondrogenesis and bone mass. We may define a novel therapeutic target for treatment of skeletal diseases, such as chondrodysplasia and osteoporosis.Xiaohao WuMinghao QuWeiyuan GongChunlei ZhouYumei LaiGuozhi XiaoElsevierarticleKindlin-2OsteoprogenitorSkeletogenesisChondrodysplasiaLow-turnover osteopeniaDiseases of the musculoskeletal systemRC925-935ENJournal of Orthopaedic Translation, Vol 32, Iss , Pp 41-48 (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	Kindlin-2 Osteoprogenitor Skeletogenesis Chondrodysplasia Low-turnover osteopenia Diseases of the musculoskeletal system RC925-935
spellingShingle	Kindlin-2 Osteoprogenitor Skeletogenesis Chondrodysplasia Low-turnover osteopenia Diseases of the musculoskeletal system RC925-935 Xiaohao Wu Minghao Qu Weiyuan Gong Chunlei Zhou Yumei Lai Guozhi Xiao Kindlin-2 deletion in osteoprogenitors causes severe chondrodysplasia and low-turnover osteopenia in mice
description	Background: Our recent studies demonstrate that the focal adhesion protein Kindlin-2 exerts crucial functions in the mesenchymal stem cells, mature osteoblasts and osteocytes in control of early skeletal development and bone homeostasis in mice. However, whether Kindlin-2 plays a role in osteoprogenitors remains unclear. Materials and methods: Mice lacking Kindlin-2 expression in osterix (Osx)-expressing cells (i.e., osteoprogenitors) were generated. Micro-computerized tomography (μCT) analyses, histology, bone histomorphometry and immunohistochemistry were performed to determine the effects of Kindlin-2 deletion on skeletal development and bone mass accrual and homeostasis. Bone marrow stromal cells (BMSCs) from mutant mice (Kindlin-2fl/fl; OsxCre) and control littermates were isolated and determined for their osteoblastic differentiation capacity. Results: Kindlin-2 was highly expressed in osteoprogenitors during endochondral ossification. Deleting Kindlin-2 expression in osteoprogenitors impaired both intramembranous and endochondral ossifications. Mutant mice displayed multiple severe skeletal abnormalities, including unmineralized fontanel, limb shortening and growth retardation. Deletion of Kindlin-2 in osteoprogenitors impaired the growth plate development and largely delayed formation of the secondary ossification center in the long bones. Furthermore, adult mutant mice displayed a severe low-turnover osteopenia with a dramatic decrease in bone formation which exceeded that in bone resorption. Primary BMSCs isolated from mutant mice exhibited decreased osteoblastic differentiation capacity. Conclusions: Our study demonstrates an essential role of Kinlind-2 expression in osteoprogenitors in regulating skeletogenesis and bone mass accrual and homeostasis in mice. The translational potential of this article: This study reveals that Kindlin-2 through its expression in osteoprogenitor cells controls chondrogenesis and bone mass. We may define a novel therapeutic target for treatment of skeletal diseases, such as chondrodysplasia and osteoporosis.
format	article
author	Xiaohao Wu Minghao Qu Weiyuan Gong Chunlei Zhou Yumei Lai Guozhi Xiao
author_facet	Xiaohao Wu Minghao Qu Weiyuan Gong Chunlei Zhou Yumei Lai Guozhi Xiao
author_sort	Xiaohao Wu
title	Kindlin-2 deletion in osteoprogenitors causes severe chondrodysplasia and low-turnover osteopenia in mice
title_short	Kindlin-2 deletion in osteoprogenitors causes severe chondrodysplasia and low-turnover osteopenia in mice
title_full	Kindlin-2 deletion in osteoprogenitors causes severe chondrodysplasia and low-turnover osteopenia in mice
title_fullStr	Kindlin-2 deletion in osteoprogenitors causes severe chondrodysplasia and low-turnover osteopenia in mice
title_full_unstemmed	Kindlin-2 deletion in osteoprogenitors causes severe chondrodysplasia and low-turnover osteopenia in mice
title_sort	kindlin-2 deletion in osteoprogenitors causes severe chondrodysplasia and low-turnover osteopenia in mice
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/fbc0cfc1cd364b4abc6632951716dc92
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Kindlin-2 deletion in osteoprogenitors causes severe chondrodysplasia and low-turnover osteopenia in mice

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