Alteration of mineral crystallinity and collagen cross-linking of bones in osteopetrotic toothless (tl/tl) rats and their improvement after treatment with colony stimulating factor-1

Wójtowicz, Andrzej; Dziedzic‐Goclawska, A.; Kamiński, Artur; Stachowicz, W.; Wójtowicz, Krzysztof; Marks, Sandy C.; Yamauchi, Mitsuo

doi:10.1016/s8756-3282(96)00336-5

Cited by 33 publications

(24 citation statements)

References 19 publications

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“…The reduced level of bone turnover in the mutant bones allows the collagen fibrils to mature in the tissue, i.e., once the telopeptideyl lysine and hydroxy-lysine residues are converted to aldehyde by the action of lysyl oxidase, the subsequent divalent and trivalent cross-link reactions are non-enzymatic and spontaneous [53]. This notion is supported by a similar cross-link phenotype seen in toothless (tl/tl) osteopetrotic rats and WBN/ Kob diabetic rats in which bone remodeling is diminished [54]. The relatively small changes in collagen cross-links that we observed in bones from cKO mice could be due to the fact that the analysis was done on the whole bone.…”

Section: Discussionmentioning

confidence: 99%

Loss of BMP signaling through BMPR1A in osteoblasts leads to greater collagen cross-link maturation and material-level mechanical properties in mouse femoral trabecular compartments

Zhang

McNerny

Terajima

et al. 2016

Bone

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Bone morphogenetic protein (BMP) signaling pathways play critical roles in skeletal development and new bone formation. Our previous study, however, showed a negative impact of BMP signaling on bone mass because of the osteoblast-specific loss of a BMP receptor (i.e. BMPR1A) showing increased trabecular bone volume and mineral density in mice. Here, we investigated the bone quality and biomechanical properties of the higher bone mass associated with BMPR1A deficiency using the osteoblast-specific Bmpr1a conditional knockout (cKO) mouse model. Collagen biochemical analysis revealed greater levels of the mature cross-link pyridinoline in the cKO bones, in parallel with upregulation of collagen modifying enzymes. Raman spectroscopy distinguished increases in the mature to immature cross-link ratio and mineral to matrix ratio in the trabecular compartments of cKO femora, but not in the cortical compartments. The mineral crystallinity was unchanged in the cKO in either the trabecular or cortical compartments. Further, we tested the intrinsic material properties by nanoindentation and found significantly higher hardness and elastic modulus in the cKO trabecular compartments, but not in the cortical compartments. Four point bending tests of cortical compartments showed lower structural biomechanical properties (i.e. strength and stiffness) in the cKO bones due to the smaller cortical areas. However, there were no significant differences in biomechanical performance at the material level, which was consistent with the nanoindentation test results on the cortical compartment. These studies emphasize the pivotal role of BMPR1A in the determination of bone quality and mechanical integrity under physiological conditions, with different impact on femoral cortical and trabecular compartments.

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Section: Discussionmentioning

confidence: 99%

Loss of BMP signaling through BMPR1A in osteoblasts leads to greater collagen cross-link maturation and material-level mechanical properties in mouse femoral trabecular compartments

Zhang

McNerny

Terajima

et al. 2016

Bone

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“…The proteoglycan form of CSF-1 binds to extracellular matrix proteins and has been identified in pepsin extracted bone collagen [32]. The ability of CSF-1 to normalize collagen cross-links and mineral crystallinity has been shown in CSF-1 deficient tl/tl rats injected with CSF-1 [33]. Matrix integrity is also influenced by hydration that is dependent on the vascular bed [34].…”

Section: Discussionmentioning

confidence: 99%

Meox2Cre-mediated disruption of CSF-1 leads to osteopetrosis and osteocyte defects

Harris

MacDougall

Horn

et al. 2012

Bone

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CSF-1, a key regulator of mononuclear phagocyte production, is highly expressed in the skeleton by osteoblasts/osteocytes and in a number of nonskeletal tissues such as uterus, kidney and brain. The spontaneous mutant op/op mouse has been the conventional model of CSF-1 deficiency and exhibits a pleiotropic phenotype characterized by osteopetrosis, and defects in hematopoiesis, fertility and neural function. Studies to further delineate the biologic effect of CSF-1 within various tissues have been hampered by the lack of suitable models. To address this issue, we generated CSF-1 floxed/floxed mice and demonstrate that Cre-mediated recombination using Meox2Cre, a Cre line expressed in epiblast during early embryogenesis, results in mice with ubiquitous CSF-1 deficiency (CSF-1KO). Homozygous CSF-1KO mice lacked CSF-1 in all tissues and displayed, in part, a similar phenotype to op/op mice that included: failure of tooth eruption, osteopetrosis, reduced macrophage densities in reproductive and other organs and altered hematopoiesis with decreased marrow cellularity, circulating monocytes and B cell lymphopoiesis. In contrast to op/op mice, CSF-1KO mice showed elevated circulating and splenic T cells. A striking feature in CSF-1KO mice was defective osteocyte maturation, bone mineralization and osteocyte-lacunar system that was associated with reduced dentin matrix protein 1 (DMP1) expression in osteocytes. CSF-1KO mice also showed a dramatic reduction in osteomacs along the endosteal surface that may have contributed to the hematopoietic and cortical bone defects. Thus, our findings show that ubiquitous CSF-1 gene deletion using a Cre-based system recapitulates the expected osteopetrotic phenotype. Moreover, results point to a novel link between CSF-1 and osteocyte survival/function that is essential for maintaining bone mass and strength during skeletal development.

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“…This increase in collagen cross-link maturation was significantly negatively correlated with an activation frequency reflecting bone remodeling (r=−0.527, p<0.01) [76]. Additionally, low bone turnover animal models, such as osteopetrotic toothless rats with osteoclast dysfunction [109] and spontaneously WBN/Kob diabetic rats with significantly low levels of bone turnover markers [74], showed a relatively higher ratio of mature pyridinium to immature cross-links. Another possible explanation for the low content of mature crosslinks in bone is that mineralization of the collagenous matrix itself may inhibit conversion of immature divalent cross-links to mature trivalent cross-links, although this…”

Section: Collagen Maturation In Terms Of Cross-link Formation In Bonementioning

confidence: 94%

Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus

2009

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Collagen cross-linking, a major post-translational modification of collagen, plays important roles in the biological and biomechanical features of bone. Collagen cross-links can be divided into lysyl hydroxylase and lysyloxidase-mediated enzymatic immature divalent cross-links,mature trivalent pyridinoline and pyrrole cross-links, and glycation- or oxidation-induced non-enzymatic cross-links(advanced glycation end products) such as glucosepane and pentosidine. These types of cross-links differ in the mechanism of formation and in function. Material properties of newly synthesized collagen matrix may differ in tissue maturity and senescence from older matrix in terms of crosslink formation. Additionally, newly synthesized matrix in osteoporotic patients or diabetic patients may not necessarily be as well-made as age-matched healthy subjects. Data have accumulated that collagen cross-link formation affects not only the mineralization process but also microdamage formation. Consequently, collagen cross-linking is thought to affect the mechanical properties of bone. Furthermore,recent basic and clinical investigations of collagen cross-links seem to face a new era. For instance, serum or urine pentosidine levels are now being used to estimate future fracture risk in osteoporosis and diabetes. In this review, we describe age-related changes in collagen cross-links in bone and abnormalities of cross-links in osteoporosis and diabetes that have been reported in the literature.

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Alteration of mineral crystallinity and collagen cross-linking of bones in osteopetrotic toothless (tl/tl) rats and their improvement after treatment with colony stimulating factor-1

Cited by 33 publications

References 19 publications

Loss of BMP signaling through BMPR1A in osteoblasts leads to greater collagen cross-link maturation and material-level mechanical properties in mouse femoral trabecular compartments

Loss of BMP signaling through BMPR1A in osteoblasts leads to greater collagen cross-link maturation and material-level mechanical properties in mouse femoral trabecular compartments

Meox2Cre-mediated disruption of CSF-1 leads to osteopetrosis and osteocyte defects

Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus

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