title: Dmp1Null Mice Develop a Unique Osteoarthritis-like Phenotype.
abstract: Patients with hypophosphatemia rickets (includingDMP1mutations) develop severe osteoarthritis (OA), although the mechanism is largely unknown. In this study, we first identified the expression of DMP1 in hypertrophic chondrocytes using immunohistochemistry (IHC) and X-gal analysis ofDmp1-knockout-lacZ-knockin heterozygous mice. Next, we characterized the OA-like phenotype inDmp1null mice from 7-week-old to one-year-old using multiple techniques, including X-ray, micro-CT, H&E staining, Goldner staining, scanning electronic microscopy, IHC assays, etc. We found a classical OA-like phenotype inDmp1null mice such as articular cartilage degradation, osteophyte formation, and subchondral osteosclerosis. TheseDmp1null mice also developed unique pathological changes, including a biphasic change in their articular cartilage from the initial expansion of hypertrophic chondrocytes at the age of 1-month to a quick diminished articular cartilage layer at the age of 3-months. Further, these null mice displayed severe enlarged knees and poorly formed bone with an expanded osteoid area. To address whether DMP1 plays a direct role in the articular cartilage, we deletedDmp1specifically in hypertrophic chondrocytes by crossing theDmp1-loxP mice with Col X Cre mice. Interestingly, these conditional knockout mice didn't display notable defects in either the articular cartilage or the growth plate. Because of the hypophosphatemia remained in the entire life span of theDmp1null mice, we also investigated whether a high phosphate diet would improve the OA-like phenotype. A 8-week treatment of a high phosphate diet significantly rescued the OA-like defect inDmp1null mice, supporting the critical role of phosphate homeostasis in maintaining the healthy joint morphology and function. Taken together, this study demonstrates a unique OA-like phenotype inDmp1null mice, but a lack of the direct impact of DMP1 on chondrogenesis. Instead, the regulation of phosphate homeostasis by DMP1 via the axis of "FGF23-renal phosphorus reabsorption" is vital for maintaining a healthy joint.
authors.affiliation: Department of Endondontics, School & Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, China;; Department of Biomedical Sciences, Texas A&M College of Dentistry, Dallas, TX, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Biomedical Sciences, Texas A&M College of Dentistry, Dallas, TX, USA;; Department of Prosthodontics, Ninth People's Hospital affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
authors.forename: Shuxian
authors.initials: S
authors.lastname: Lin
authors.affiliation: Department of Biomedical Sciences, Texas A&M College of Dentistry, Dallas, TX, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.
authors.forename: Baozhi
authors.initials: B
authors.lastname: Yuan
authors.affiliation: Department of Periodontics, UT Health Science Center, San Antonio, TX, USA.
authors.forename: Steph E
authors.initials: SE
authors.lastname: Harris
authors.affiliation: Department of Biomedical Sciences, Texas A&M College of Dentistry, Dallas, TX, USA.
authors.forename: Jian Q
authors.initials: JQ
authors.lastname: Feng
mesh_terms: D000375:Aging / Q000235:genetics / Q000502:physiology; D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D016326:Extracellular Matrix Proteins / Q000172:deficiency* / Q000235:genetics; D000089703:Fibroblast Growth Factor-23; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008855:Microscopy, Electron, Scanning; D010003:Osteoarthritis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D016226:Phosphorus, Dietary / Q000627:therapeutic use*; D055114:X-Ray Microtomography
chemical_list: C513308:Dmp1 protein, mouse; D016326:Extracellular Matrix Proteins; C000717428:Fgf23 protein, mouse; D016226:Phosphorus, Dietary; D000089703:Fibroblast Growth Factor-23
keywords: Cartilage; Chondrocyte; Dentin Matrix Protein 1; Osteoarthritis; Subchondral Bone.