Selective Pyk2 inhibition enhances bone restoration through SCARA5-mediated bone marrow remodeling in ovariectomized mice
Abstract Understanding the intricate cellular interactions involved in bone restoration is crucial for developing effective strategies to promote bone healing and mitigate conditions such as osteoporosis and fractures. Here, we provide compelling evidence supporting the anabolic effects of a pharmac...
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BMC
2024-11-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-024-01945-8 |
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| author | Yunqing Liu Mai Nishiura Mika Fujii Sumiti Sandhu Yasutaka Yawaka Yutaka Yamazaki Akira Hasebe Tadahiro Iimura Sek Won Kong Ji-Won Lee |
| author_facet | Yunqing Liu Mai Nishiura Mika Fujii Sumiti Sandhu Yasutaka Yawaka Yutaka Yamazaki Akira Hasebe Tadahiro Iimura Sek Won Kong Ji-Won Lee |
| author_sort | Yunqing Liu |
| collection | DOAJ |
| description | Abstract Understanding the intricate cellular interactions involved in bone restoration is crucial for developing effective strategies to promote bone healing and mitigate conditions such as osteoporosis and fractures. Here, we provide compelling evidence supporting the anabolic effects of a pharmacological Pyk2 inhibitor (Pyk2-Inh) in promoting bone restoration. In vitro, Pyk2 signaling inhibition markedly enhances alkaline phosphatase (ALP) activity, a hallmark of osteoblast differentiation, through activation of canonical Wnt/β-catenin signaling. Notably, analysis of human mesenchymal stem cells through RNA-seq revealed a novel candidate, SCARA5, identified through Pyk2-Inh treatment. We demonstrate that Scara5 plays a crucial role in suppressing the differentiation from stromal cells into adipocytes, and accelerates lineage commitment to osteoblasts, establishing Scara5 as a negative regulator of bone formation. Additionally, Pyk2 inhibition significantly impedes osteoclast differentiation and bone resorption. In a co-culture system comprising osteoblasts and osteoclasts, Pyk2-Inh effectively suppressed osteoclast differentiation, accompanied by a substantial increase in the transcriptional expression of Tnfrsf11b and Csf1 in osteoblasts, highlighting a dual regulatory role in osteoblast-osteoclast crosstalk. In an ovariectomized mouse model of osteoporosis, oral administration of Pyk2-Inh significantly increased bone mass by simultaneously reducing bone resorption, promoting bone formation and decreasing bone marrow fat. These results suggest Pyk2 as a potential therapeutic target for both adipogenesis and osteogenesis in bone marrow. Our findings underscore the importance of Pyk2 signaling inhibition as a key regulator of bone remodeling, offering promising prospects for the development of novel osteoporosis therapies. |
| format | Article |
| id | doaj-art-6067f1f0488844c1883abcaf1a93aaf9 |
| institution | OA Journals |
| issn | 1478-811X |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj-art-6067f1f0488844c1883abcaf1a93aaf92025-08-20T02:22:33ZengBMCCell Communication and Signaling1478-811X2024-11-0122111710.1186/s12964-024-01945-8Selective Pyk2 inhibition enhances bone restoration through SCARA5-mediated bone marrow remodeling in ovariectomized miceYunqing Liu0Mai Nishiura1Mika Fujii2Sumiti Sandhu3Yasutaka Yawaka4Yutaka Yamazaki5Akira Hasebe6Tadahiro Iimura7Sek Won Kong8Ji-Won Lee9Department of Pharmacology, Faculty and Graduate School of Dental Medicine, Hokkaido UniversityDepartment of Pharmacology, Faculty and Graduate School of Dental Medicine, Hokkaido UniversityDepartment of Oral Health Science, Gerodontology, Faculty of Dental Medicine, Hokkaido UniversityComputational Health and Informatics Program, Boston Children’s HospitalDentistry for Children and Disabled Persons, Department of Oral Functional Science, Faculty of Dental Medicine, Hokkaido UniversityDepartment of Oral Health Science, Gerodontology, Faculty of Dental Medicine, Hokkaido UniversityDepartment of Oral Pathobiological Science, Microbiology, Graduate School of Dental Medicine, Hokkaido UniversityDepartment of Pharmacology, Faculty and Graduate School of Dental Medicine, Hokkaido UniversityComputational Health and Informatics Program, Boston Children’s HospitalDepartment of Oral Pathobiological Science, Microbiology, Graduate School of Dental Medicine, Hokkaido UniversityAbstract Understanding the intricate cellular interactions involved in bone restoration is crucial for developing effective strategies to promote bone healing and mitigate conditions such as osteoporosis and fractures. Here, we provide compelling evidence supporting the anabolic effects of a pharmacological Pyk2 inhibitor (Pyk2-Inh) in promoting bone restoration. In vitro, Pyk2 signaling inhibition markedly enhances alkaline phosphatase (ALP) activity, a hallmark of osteoblast differentiation, through activation of canonical Wnt/β-catenin signaling. Notably, analysis of human mesenchymal stem cells through RNA-seq revealed a novel candidate, SCARA5, identified through Pyk2-Inh treatment. We demonstrate that Scara5 plays a crucial role in suppressing the differentiation from stromal cells into adipocytes, and accelerates lineage commitment to osteoblasts, establishing Scara5 as a negative regulator of bone formation. Additionally, Pyk2 inhibition significantly impedes osteoclast differentiation and bone resorption. In a co-culture system comprising osteoblasts and osteoclasts, Pyk2-Inh effectively suppressed osteoclast differentiation, accompanied by a substantial increase in the transcriptional expression of Tnfrsf11b and Csf1 in osteoblasts, highlighting a dual regulatory role in osteoblast-osteoclast crosstalk. In an ovariectomized mouse model of osteoporosis, oral administration of Pyk2-Inh significantly increased bone mass by simultaneously reducing bone resorption, promoting bone formation and decreasing bone marrow fat. These results suggest Pyk2 as a potential therapeutic target for both adipogenesis and osteogenesis in bone marrow. Our findings underscore the importance of Pyk2 signaling inhibition as a key regulator of bone remodeling, offering promising prospects for the development of novel osteoporosis therapies.https://doi.org/10.1186/s12964-024-01945-8Pyk2BoneMesenchymal stem cellOsteoclastOsteoblastAdipocyte |
| spellingShingle | Yunqing Liu Mai Nishiura Mika Fujii Sumiti Sandhu Yasutaka Yawaka Yutaka Yamazaki Akira Hasebe Tadahiro Iimura Sek Won Kong Ji-Won Lee Selective Pyk2 inhibition enhances bone restoration through SCARA5-mediated bone marrow remodeling in ovariectomized mice Cell Communication and Signaling Pyk2 Bone Mesenchymal stem cell Osteoclast Osteoblast Adipocyte |
| title | Selective Pyk2 inhibition enhances bone restoration through SCARA5-mediated bone marrow remodeling in ovariectomized mice |
| title_full | Selective Pyk2 inhibition enhances bone restoration through SCARA5-mediated bone marrow remodeling in ovariectomized mice |
| title_fullStr | Selective Pyk2 inhibition enhances bone restoration through SCARA5-mediated bone marrow remodeling in ovariectomized mice |
| title_full_unstemmed | Selective Pyk2 inhibition enhances bone restoration through SCARA5-mediated bone marrow remodeling in ovariectomized mice |
| title_short | Selective Pyk2 inhibition enhances bone restoration through SCARA5-mediated bone marrow remodeling in ovariectomized mice |
| title_sort | selective pyk2 inhibition enhances bone restoration through scara5 mediated bone marrow remodeling in ovariectomized mice |
| topic | Pyk2 Bone Mesenchymal stem cell Osteoclast Osteoblast Adipocyte |
| url | https://doi.org/10.1186/s12964-024-01945-8 |
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