{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:45:27Z","timestamp":1760402727159,"version":"build-2065373602"},"reference-count":58,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,1,15]],"date-time":"2022-01-15T00:00:00Z","timestamp":1642204800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Ossification of the posterior longitudinal ligament (OPLL), a disease characterized by the ectopic ossification of a spinal ligament, promotes neurological disorders associated with spinal canal stenosis. While blocking ectopic ossification is mandatory to prevent OPLL development and progression, the mechanisms underlying the condition remain unknown. Here we show that expression of hydroxyacid oxidase 1 (Hao1), a gene identified in a previous genome-wide association study (GWAS) as an OPLL-associated candidate gene, specifically and significantly decreased in fibroblasts during osteoblast differentiation. We then newly established Hao1-deficient mice by generating Hao1-flox mice and crossing them with CAG-Cre mice to yield global Hao1-knockout (CAG-Cre\/Hao1flox\/flox; Hao1 KO) animals. Hao1 KO mice were born normally and exhibited no obvious phenotypes, including growth retardation. Moreover, Hao1 KO mice did not exhibit ectopic ossification or calcification. However, urinary levels of some metabolites of the tricarboxylic acid (TCA) cycle were significantly lower in Hao1 KO compared to control mice based on comprehensive metabolomic analysis. Our data indicate that Hao1 loss does not promote ectopic ossification, but rather that Hao1 functions to regulate the TCA cycle in vivo.<\/jats:p>","DOI":"10.3390\/metabo12010082","type":"journal-article","created":{"date-parts":[[2022,1,16]],"date-time":"2022-01-16T20:45:21Z","timestamp":1642365921000},"page":"82","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Hao1 Is Not a Pathogenic Factor for Ectopic Ossifications but Functions to Regulate the TCA Cycle In Vivo"],"prefix":"10.3390","volume":"12","author":[{"given":"Atsushi","family":"Kimura","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0440-6820","authenticated-orcid":false,"given":"Akiyoshi","family":"Hirayama","sequence":"additional","affiliation":[{"name":"Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka 997-0052, Yamagata, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatsuaki","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuiko","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan"},{"name":"Department of Advanced Therapy for Musculoskeletal Disorders II, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan"},{"name":"Department of Musculoskeletal Reconstruction and Regeneration Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tami","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan"},{"name":"Department of Advanced Therapy for Musculoskeletal Disorders II, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan"},{"name":"Department of Musculoskeletal Reconstruction and Regeneration Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satsuki","family":"Ikeda","sequence":"additional","affiliation":[{"name":"Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka 997-0052, Yamagata, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Midori","family":"Maruyama","sequence":"additional","affiliation":[{"name":"Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka 997-0052, Yamagata, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mari","family":"Kaneko","sequence":"additional","affiliation":[{"name":"Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Hyogo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mayo","family":"Shigeta","sequence":"additional","affiliation":[{"name":"Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Hyogo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eri","family":"Ito","sequence":"additional","affiliation":[{"name":"Institute for Integrated Sports Medicine, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoya","family":"Soma","sequence":"additional","affiliation":[{"name":"Department of Dentistry and Oral Surgery, Division of Oral and Maxillofacial Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kana","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9502-2509","authenticated-orcid":false,"given":"Tomoyoshi","family":"Soga","sequence":"additional","affiliation":[{"name":"Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka 997-0052, Yamagata, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaru","family":"Tomita","sequence":"additional","affiliation":[{"name":"Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka 997-0052, Yamagata, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akihito","family":"Oya","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Morio","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2279-7028","authenticated-orcid":false,"given":"Masaya","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arihiko","family":"Kanaji","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan"},{"name":"Department of Advanced Therapy for Musculoskeletal Disorders II, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan"},{"name":"Department of Musculoskeletal Reconstruction and Regeneration Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan"},{"name":"Department of Orthopedic Surgery, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,15]]},"reference":[{"key":"ref_1","first-page":"168","article-title":"Pathogenesis of myelopathy in patients with ossification of the posterior longitudinal 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