{"id":"bc2bbdf0-4582-5c4b-9d0c-39eab92121f5","stable_key":"44737fa3-b335-53f4-a644-b9878d4416ac:creatine-tnap-pocket-bone","predicate":"pocket_variants_reduced","statement":"Human missense variants in the glycerol pocket reduced TNAP-dependent mineralization in vitro and were associated with lower alkaline phosphatase activity and bone mineral density.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"context_dependent","is_public":true,"mechanism_event_id":"145e1769-07a2-5c83-b8a1-c39ac4982789","mechanism_event_label":"A shared protein connects the fat-energy pathway to bone biology; this is not evidence that creatine repairs those variants.","subject":{"id":"3148c377-9b4c-56ca-bc36-081bf1905d57","slug":"alpl","display_name":"Tissue-nonspecific alkaline phosphatase ALPL / TNAP","entity_type_key":"protein"},"object":{"id":"f5092ce6-54c3-55a4-a373-b33dc3b4fe8c","slug":"osteoblast-mineralization","display_name":"Osteoblast mineralization","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"145e1769-07a2-5c83-b8a1-c39ac4982789","stable_key":"44737fa3-b335-53f4-a644-b9878d4416ac:creatine-tnap-pocket-bone-event","event_type":"biochemical_relationship","label":"A shared protein connects the fat-energy pathway to bone biology; this is not evidence that creatine repairs those variants.","description":"Human missense variants in the glycerol pocket reduced TNAP-dependent mineralization in vitro and were associated with lower alkaline phosphatase activity and bone mineral density.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"af8eada2-0a93-5943-b1d9-8ee9ac68f8ee","slug":"glycerol","display_name":"Glycerol","entity_type_key":"small_molecule"},"role":"regulatory_ligand","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"3148c377-9b4c-56ca-bc36-081bf1905d57","slug":"alpl","display_name":"Tissue-nonspecific alkaline phosphatase ALPL / TNAP","entity_type_key":"protein"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"f5092ce6-54c3-55a4-a373-b33dc3b4fe8c","slug":"osteoblast-mineralization","display_name":"Osteoblast mineralization","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""}]},"contexts":[{"dimension":"availability_state","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null},{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/creatine-research/42020733.abstract.txt\", \"locator\": \"Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"232795a0a16f2f2445cd43c34e4542fb2470eefb41f72fa9dc655991dbd772fd\", \"start_char\": 0, \"end_char\": 1255, \"text_sha256\": \"232795a0a16f2f2445cd43c34e4542fb2470eefb41f72fa9dc655991dbd772fd\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Structural, biochemical, cellular, physiological and human genetic experiments","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Glycerol binding and glycerol-pocket disruption","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Published 2026; model-specific thermogenesis and mineralization findings do not establish a dietary glycerol or creatine treatment for bone disease.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Creatine research collection; topical membership is not evidence of a direct dietary effect.","comparator":null,"unit":null,"notes":"","entity":{"slug":"creatine","display_name":"Creatine","entity_type_key":"small_molecule"}},{"dimension":"organism","value_text":"TNAP experimental systems, mice and human variant analyses","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"A shared protein connects the fat-energy pathway to bone biology; this is not evidence that creatine repairs those variants.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[creatine-p42020733] Glycerol-driven TNAP activation in thermogenesis and mineralization. (2026). https://pubmed.ncbi.nlm.nih.gov/42020733/ DOI: 10.1038/s41586-026-10396-9","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Thermogenic adipocytes, osteoblasts and purified protein","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"trigger_kind","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null}],"evidence":[{"id":"2ce9feaa-dd6b-57da-8a33-61c26c935ab5","evidence_kind":"source_excerpt","locator":"Lines 568-579","start_line":568,"end_line":579,"excerpt":"### creatine-tnap-pocket-bone\nHuman missense variants in the glycerol pocket reduced TNAP-dependent mineralization in vitro and were associated with lower alkaline phosphatase activity and bone mineral density.\nCondition category: machinery_impairment\nnutrient_topic: Creatine research collection; topical membership is not evidence of a direct dietary effect.\nplain_language: A shared protein connects the fat-energy pathway to bone biology; this is not evidence that creatine repairs those variants.\norganism: TNAP experimental systems, mice and human variant analyses\ntissue_or_cell_type: Thermogenic adipocytes, osteoblasts and purified protein\nexperimental_model: Structural, biochemical, cellular, physiological and human genetic experiments\nlimitations: Published 2026; model-specific thermogenesis and mineralization findings do not establish a dietary glycerol or creatine treatment for bone disease.\nexposure: Glycerol binding and glycerol-pocket disruption\nevidence_span: {\"source_cache\": \"artifacts/creatine-research/42020733.abstract.txt\", \"locator\": \"Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"232795a0a16f2f2445cd43c34e4542fb2470eefb41f72fa9dc655991dbd772fd\", \"start_char\": 0, \"end_char\": 1255, \"text_sha256\": \"232795a0a16f2f2445cd43c34e4542fb2470eefb41f72fa9dc655991dbd772fd\"}\n[creatine-p42020733] Glycerol-driven TNAP activation in thermogenesis and mineralization. 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