Studies on the phenotype and function of osteoclasts using osteopetrotic and rachitic animal models
Author: Hollberg, Karin
Date: 2007-09-28
Location: Seminarierum 2, F-huset, Karolinska Universitetssjukhuset, Huddinge
Time: 10.00
Department: Institutionen för laboratoriemedicin / Department of Laboratory Medicine
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thesis.pdf (1.428Mb)
Abstract
Osteoclasts are multinucleated bone-resorbing cells that have been
implicated in a variety of skeletal diseases e.g. osteoporosis,
rheumatoid arthritis and skeletal metastasis. Under physiological
conditions, the osteoclast participates in ossification during
longitudinal bone growth as well as in bone remodelling during adulthood.
Bone resorption is initiated by attachment of osteoclasts to the surface
of bone to be resorbed by interaction with mineral-associated adhesive
proteins. This interaction also drives formation of specialized membrane
domains called ruffled borders and sealing zones leading to cell
polarization necessary for enclosement of the degradative process in a
discrete extracellular area. In this resorption lacuna, local
acidification leads to dissolution of mineral, and secretion of
proteolytic enzymes e.g. cathepsin K (Ctsk) and matrix metalloproteinase
(MMP)-9 completes degradation of the exposed collagen. Another secreted
osteoclast enzyme, tartrate-resistant acid phosphatase (TRAP), is a
protein phosphatase with suggested roles in regulating osteoclast
adhesion, migration and matrix degradation.
In this thesis, animal models with the skeletal diseases rickets and
osteopetrosis were employed to study the relation between ultrastructural
morphological characteristics of osteoclasts and secretion of biochemical
resorption markers e.g. Ctsk, MMP-9 and TRAP. Using two different models
of rickets e.g. induced by dietary restriction of phosphate and vitamin D
in young rats and transgenic mice overexpressing the phosphate-regulating
FGF-23 in osteoblasts, it was demonstrated that mineralization of bone
matrix is required for osteoclast polarization but not for secretion of
proteolytic enzymes and that matrix mineralization is protective for and
limits collagen degradation. It is concluded that the validity of
osteoclast polarization as an ultrastructural morphological indicator of
osteoclast resorptive activity is restricted to bone with normal
mineralization. Moreover, genes encoding mineralization-promoting
proteins are activated in osteoblasts from mice with hypophosphatemic
rickets, indicative of a compensatory mechanism to favour mineralization.
TRAP is synthesized as an inactive monomeric precursor requiring
proteolytic processing to become an active enzyme. Proteolytic processing
of TRAP was altered in a subpopulation of metaphyseal osteoclasts in a
mouse strain where the Ctsk gene was inactivated, implicating Ctsk as a
regulator of TRAP processing in vivo and supporting the concept of
functional heterogeneity of osteoclasts depending on their precise
anatomical localization within the skeleton. Moreover, the intracellular
distribution and secretion of monomeric and proteolytically processed
TRAP was altered in Ctsk-deficient osteoclasts, providing evidence for a
novel role for Ctsk in the regulation of intracellular membrane traffic
in osteoclasts. The possibility that TRAP is the common denominator for
this vesicular transport regulation was indicated by the observation of
an accumulation of cytoplasmic vesicles in osteoclasts from mice with an
inactivated TRAP gene. In addition, whereas Ctsk was secreted by both
polarized and non-polarized osteoclasts, TRAP was secreted only by
polarized osteoclasts under certain conditions, suggesting different
regulation for secretion of these enzymes as well as an action of TRAP
later than Ctsk in the matrix degradative phase of the resorption
sequence.
List of papers:
I. Hollberg K, Nordahl J, Hultenby K, Mengarelli-Widholm S, Andersson G, Reinholt FP (2005). "Polarization and secretion of cathepsin K precede tartrate-resistant acid phosphatase secretion to the ruffled border area during the activation of matrix-resorbing clasts." J Bone Miner Metab 23(6): 441-9
Pubmed
II. Hollberg K, Marsell R, Norgård M, Larsson T, Jonsson KB, Andersson G (2007). "Osteoclasts in rachitic FGF-23 transgenic mice efficiently degrade bone matrix." (Submitted)
III. Hollberg K, Hultenby K, Hayman A, Cox T, Andersson G (2002). "Osteoclasts from mice deficient in tartrate-resistant acid phosphatase have altered ruffled borders and disturbed intracellular vesicular transport." Exp Cell Res 279(2): 227-38
Pubmed
IV. Zenger S, Hollberg K, Ljusberg J, Norgård M, Ek-Rylander B, Kiviranta R, Andersson G (2007). "Proteolytic processing and polarized secretion of tartrate-resistant acid phosphatase is altered in a subpopulation of metaphyseal osteoclasts in cathepsin K-deficient mice." Bone Jul 19: Epub ahead of print
Pubmed
I. Hollberg K, Nordahl J, Hultenby K, Mengarelli-Widholm S, Andersson G, Reinholt FP (2005). "Polarization and secretion of cathepsin K precede tartrate-resistant acid phosphatase secretion to the ruffled border area during the activation of matrix-resorbing clasts." J Bone Miner Metab 23(6): 441-9
Pubmed
II. Hollberg K, Marsell R, Norgård M, Larsson T, Jonsson KB, Andersson G (2007). "Osteoclasts in rachitic FGF-23 transgenic mice efficiently degrade bone matrix." (Submitted)
III. Hollberg K, Hultenby K, Hayman A, Cox T, Andersson G (2002). "Osteoclasts from mice deficient in tartrate-resistant acid phosphatase have altered ruffled borders and disturbed intracellular vesicular transport." Exp Cell Res 279(2): 227-38
Pubmed
IV. Zenger S, Hollberg K, Ljusberg J, Norgård M, Ek-Rylander B, Kiviranta R, Andersson G (2007). "Proteolytic processing and polarized secretion of tartrate-resistant acid phosphatase is altered in a subpopulation of metaphyseal osteoclasts in cathepsin K-deficient mice." Bone Jul 19: Epub ahead of print
Pubmed
Issue date: 2007-09-07
Rights:
Publication year: 2007
ISBN: 978-91-7357-313-9
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