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As essential mediators of intercellular communication, secreted proteins play a pivotal role in directing mesenchymal stem cells (MSCs) recruitment, their differentiation into osteoblasts (OBs), the proliferation and activation of these OBs, as well as the synthesis and mineralization of the bone matrix. Furthermore, they modulate angiogenesis through dynamic alterations in concentration gradients, which are meticulously timed and spatially targeted, thereby facilitating their interconnected interactions. This precise regulation ultimately underpins the repair and regeneration of functional bone tissues. Given their critical regulatory function in regeneration, secreted proteins serve as key targets in bone tissue engineering and strategies aimed at repairing bone defects. In this review, we provide a systematic overview of recent advances in the research concerning secreted proteins in regulating osteogenesis, to provide novel insights and directions to further the development of bone regenerative medicine.<\/jats:p>","DOI":"10.3389\/fcell.2026.1873387","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T05:37:28Z","timestamp":1782797848000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Decoding the secretory blueprint of bone healing: from gradients to regeneration"],"prefix":"10.3389","volume":"14","author":[{"given":"Wenxiao","family":"Yang","sequence":"first","affiliation":[{"name":"Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanfang","family":"Wang","sequence":"additional","affiliation":[{"name":"Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keda","family":"Liu","sequence":"additional","affiliation":[{"name":"Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1111\/iej.12869","article-title":"VEGF\/BMP-2 loaded three-dimensional model for enhanced angiogenic and odontogenic potential of dental pulp stem cells","volume":"51","author":"Aksel","year":"2018","journal-title":"Int. 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