uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Osteoclast polarization is not required for degradation of bone matrix in rachitic FGF23 transgenic mice
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Show others and affiliations
2008 (English)In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 42, no 6, 1111-1121 p.Article in journal (Refereed) Published
Abstract [en]

Hypophosphatemic transgenic (tg) mice overexpressing FGF23 in osteoblasts display disorganized growth plates and reduced bone mineral density characteristic of rickets/osteomalacia. These FGF23 tg mice were used as an in vivo model to examine the relation between osteoclast polarization, secretion of proteolytic enzymes and resorptive activity. Tg mice had increased mRNA expression levels of the ostcoblast differentiation marker Runx2 and mineralization-promoting proteins alkaline phosphatase and bone sialoprotein in the long bones compared to wild type (wt) mice. In contrast, expression of alpha 1 (1) collagen, osteocalcin, dentin matrix protein 1 and osteopontin was unchanged, indicating selective activation of osteoblasts promoting mineralization. The number of osteoclasts was unchanged in tg compared to wt mice, as determined by histomorphometry, serum levels of TRAP 5b activity as well as mRNA expression levels of TRAP and cathepsin K. However, tg mice displayed elevated serum concentrations of C-terminal telopeptide of collagen I (CTX) indicative of increased bone matrix degradation. The majority of osteoclasts in FGF23 tg mice lacked ultrastructural morphological signs of proper polarization. However, they secreted both cathepsin K and MMP-9 at levels comparable to osteoclasts with ruffled borders. Mineralization of bone matrix thus appears essential for inducing osteoclast polarization but not for secretion of osteoclast proteases. Finally, release of CTX by freshly isolated osteoclasts was increased on demineralized compared to mineralized bovine bone slices, indicating that the mineral component limits collagen degradation. We conclude that ruffled borders are implicated in acidification and subsequent demineralization of the bone matrix, however not required for matrix degradation. The data collectively provide evidence that osteoclasts, despite absence of ruffled borders, effectively participate in the degradation of hypomineralized bone matrix in rachitic FGF23 tg mice.

Place, publisher, year, edition, pages
2008. Vol. 42, no 6, 1111-1121 p.
Keyword [en]
rickets, osteomalacia, phosphate, FGF23, FGF-23, bone mineralization, bone resorption, osteoclasts
National Category
URN: urn:nbn:se:uu:diva-97057DOI: 10.1016/j.bone.2008.01.019ISI: 000256330000013PubMedID: 18346951OAI: oai:DiVA.org:uu-97057DiVA: diva2:171839
Available from: 2008-04-18 Created: 2008-04-18 Last updated: 2014-11-12Bibliographically approved
In thesis
1. FGF23 - a possible Phosphatonin
Open this publication in new window or tab >>FGF23 - a possible Phosphatonin
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Human physiology is dependent on an accurate phosphate (Pi) homeostasis. Defective Pi regulation causes hyper- or hypophosphatemia, which are associated with ectopic calcification or impaired bone mineralization, and a shortened life span. Current endocrine models of Pi homeostasis are incomplete. However, studies of acquired and hereditary disorders of Pi homeostasis have revealed new potential Pi regulating hormones, Phosphatonin(s). One of these is fibroblast growth factor-23 (FGF23). FGF23 is produced in bone and is secreted into the circulation. Mutations in FGF23 causes disturbed Pi regulation, without the appropriate counter-regulatory actions of parathyroid hormone or vitamin D. By the generation of FGF23 transgenic mice, which display phenotypic similarities to patients with hypophosphatemic disorders, we show that FGF23 exerts endocrine actions in the kidney and causes osteomalacia. Renal FGF23 actions severely decrease Pi reabsorption and expression of Klotho, a suggested age suppressor gene, known to be crucial in FGF23 receptor binding and activation. In bone, our transgenic model displays impaired osteoclast polarization, which should be detrimental to osteoclastic bone resorption in osteomalacia. However, in our model osteoclasts efficiently participate in bone matrix degradation. Furthermore, we investigated a large population-based cohort in order to elucidate the role of FGF23 in normal physiology. Importantly, we were able to demonstrate an association of FGF23 to parathyroid hormone, renal function and bone mineral density and we found a correlation of FGF23 to weight and body fat mass. The studies on which this thesis is based, demonstrate that FGF23 has phosphatonin-like properties and that the skeleton functions as an endocrine organ. In addition, the results indicate that FGF23 has a role in bone mineral and lipid metabolism, and that FGF23 is a possible diagnostic marker and therapeutic target for the future.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 72 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 333
Surgery, Fibroblast growth factor 23, FGF23, FGF-23, Phosphate homeostasis, Vitamin D, Klotho, Parathyroid hormone, PTH, Kirurgi
urn:nbn:se:uu:diva-8649 (URN)978-91-554-7165-1 (ISBN)
Public defence
2008-05-09, Rosénsalen, Akademiska Sjukhuset (Barnsjukhuset), Ingång 95/96, Uppsala, 09:15
Available from: 2008-04-18 Created: 2008-04-18 Last updated: 2013-12-05Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Marsell, RichardJonsson, Kenneth B
By organisation
OrthopaedicsDepartment of Medical Sciences
In the same journal

Search outside of DiVA

GoogleGoogle Scholar

Altmetric score

Total: 208 hits
ReferencesLink to record
Permanent link

Direct link