Deficiency and Also Transgenic Overexpression of Timp-3 Both Lead to Compromised Bone Mass and Architecture In Vivo

Javaheri, Behzâd; Hopkinson, Mark; Poulet, Blandine; Pollard, Andrea S.; Shefelbine, Sandra J.; Chang, Yu Mei; Francis‐West, Philippa; Bou‐Gharios, George; Pitsillides, Andrew A.

doi:10.1371/journal.pone.0159657

Cited by 17 publications

(27 citation statements)

References 57 publications

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“…Young's modulus values for the Timp-3 −/− bone demonstrated a tendency to decrease, but the high variance of these values resulted in no statistical significance compared with WT bone. The decrease in the mechanical properties of bone we observed in this study is in agreement with previous works that found compromised tissue quality and [26], cardiovascular [27], liver [10], and musculoskeletal tissue of Timp-3 −/− mice [15]. Alterations in the structure and composition of the Timp-3 −/− bone mice can explain the deficiencies observed in the mechanical properties of the Timp-3 −/− bone.…”

Section: Discussionsupporting

confidence: 92%

“…The morphological analysis of Timp-3 −/− cortical bone revealed a significant decrease in the bone volume, with thinner cortices and higher canal porosity compared with WT bone. Timp-3 −/− bones were smaller, with a reduced cross-sectional area and altered geometry (I max , I min , and J), in agreement with previous studies conducted on the tibiae of the same mouse strain [15]. The increase in the Timp-3 −/− cortical bone porosity due to the vascular channels is also in agreement with the increase in angiogenesis typical of these bones [6].…”

Section: Discussionsupporting

confidence: 90%

“…Prior research on bone demonstrated that cortical thinning and increased porosity occur when the rate of bone remodeling is altered [30,31]. In agreement with that, a recent histological analysis of Timp-3 −/− bone has found an increased osteoclasts number in TIMP-3-deficient bone, with no changes in the osteoblasts number, and no changes in the growth plate area [15]. Thus, it is possible that due to the lack of TIMP-3 in the bone, there is an unregulated MMP, ADAM, and ADAMTS activity in the tissue that leads to an increase in bone remodeling, which may, in turn, decrease cortical thickness and increase bone porosity.…”

Section: Discussionsupporting

confidence: 56%

“…Also, at the trabecular level, changes in the composition of the Timp-3 −/− bone result in the altered micro-architecture, characterized by a reduced total bone volume with an increased volume density and more, thinner, highly connected, and closely packed trabeculae: a typical configuration of a bone with high remodeling. Interestingly, the trabecular configuration we observed in the Timp-3 −/− mice is not due to improper growth plate cartilage degradation [15] rather our results suggest collagenases are predominantly responsible for altered Timp-3 −/− bone architecture through imbalanced bone remodeling.…”

Section: Discussionmentioning

confidence: 53%

“…TIMP-3-deficient mice (Timp-3 −/− ) further exhibited increased collagen degradation [9], exacerbated inflammatory process [10], osteoarthritis [9], high angiogenesis [6], abnormal vascularization [11], dilated cardiomyopathy [12], increased bronchiole branching [13], severe diabetic symptoms [14], failed liver regeneration [10], and tumor growth [6,12]. Recent studies of Timp-3 −/− bone found that they are small in size, with compromised mass and structure, and increased number of osteoclasts [15].…”

Section: Introductionmentioning

confidence: 99%

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Altered Bone Mechanics, Architecture and Composition in the Skeleton of TIMP-3-Deficient Mice

et al. 2017

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Tissue inhibitor of metalloproteinases-3 (TIMP-3) maintains a healthy extracellular matrix by regulating matrix metalloproteinases (MMP), disintegrin-metalloproteinases (ADAM), and disintegrin-metalloproteinases with ThromboSpondin-like motifs (ADAMTS) activity. Currently, there is a need for a comprehensive understanding of the effects of TIMP-3 on the bone quality and integrity. In this study, we examined the mechanical, morphological, and compositional properties of TIMP-3 knock out (Timp-3 ) mouse bone. We hypothesize that the lack of TIMP-3 plays an important role in maintaining the overall bone integrity. Mechanical properties of humeri, lumbar vertebrae, and femurs from Timp-3 mice were determined using 3-point bending, compression, and notched 3-point bending, respectively. Morphological properties of the humeral cortical and trabecular bone and the caudal vertebrae cortical bone were evaluated using micro-computed tomography, while the composition of the femoral cortical and trabecular bone was examined using Fourier transform infrared spectroscopic imaging. Our results revealed that the integrity of the Timp-3 bone is compromised due to changes in its composition, structure, and mechanics. Reductions in the yield and ultimate load and stress capacity, and loss in bone fracture toughness were attributed to reduced density and thickness, and increased porosity of cortical bone. Thin trabeculae were dense, highly connected, and closely packed in Timp-3 bone. Furthermore, altered cortical and trabecular bone mineralization and increased compositional heterogeneity were found in Timp-3 bone, all being indicative of high bone remodeling. In conclusion, this study suggests that the lack of TIMP-3 is detrimental to bone development and maintenance.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 53%

Section: Introductionmentioning

confidence: 99%

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Altered Bone Mechanics, Architecture and Composition in the Skeleton of TIMP-3-Deficient Mice

et al. 2017

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Targeted Inhibition of Aggrecanases Prevents Articular Cartilage Degradation and Augments Bone Mass in the STR/Ort Mouse Model of Spontaneous Osteoarthritis

Kanakis

Liu

Poulet

et al. 2019

Arthritis & Rheumatology

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Objective. Cartilage destruction in osteoarthritis (OA) is mediated mainly by matrix metalloproteinases (MMPs) and ADAMTS. The therapeutic candidature of targeting aggrecanases has not yet been defined in joints in which spontaneous OA arises from genetic susceptibility, as in the case of the STR/Ort mouse, without a traumatic or loadinduced etiology. In addition, we do not know the long-term effect of aggrecanase inhibition on bone. We undertook this study to assess the potential aggrecanase selectivity of a variant of tissue inhibitor of metalloproteinases 3 (TIMP-3), called [-1A]TIMP-3, on spontaneous OA development and bone formation in STR/Ort mice.Methods. Using the background of STR/Ort mice, which develop spontaneous OA, we generated transgenic mice that overexpress [-1A]TIMP-3, either ubiquitously or conditionally in chondrocytes. [-1A]TIMP-3 has an extra alanine at the N-terminus that selectively inhibits ADAMTS but not MMPs. We analyzed a range of OA-related measures in all mice at age 40 weeks.Results. Mice expressing high levels of [-1A]TIMP-3 were protected against development of OA, while those expressing low levels were not. Interestingly, we also found that high levels of [-1A]TIMP-3 transgene overexpression resulted in increased bone mass, particularly in females. This regulation of bone mass was at least partly direct, as adult mouse primary osteoblasts infected with [-1A]TIMP-3 in vitro showed elevated rates of mineralization.Conclusion. The results provide evidence that [-1A]TIMP-3-mediated inhibition of aggrecanases can protect against cartilage degradation in a naturally occurring mouse model of OA, and they highlight a novel role that aggrecanase inhibition may play in increased bone mass.

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TIMP Loss Activates Metalloproteinase-TNFα-DKK1 Axis To Compromise Wnt Signaling and Bone Mass

Chen

Aiken

Saw

et al. 2018

Journal of Bone and Mineral Research

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Deregulated proteolysis invariably underlies most human diseases including bone pathologies. Metalloproteinases constitute the largest of the five protease families, and the metzincin metalloproteinases are inhibited by the four tissue inhibitors of metalloproteinase called TIMPs. We hypothesized that Timp genes are essential for skeletal homeostasis. We bred individual Timp knockout mice to generate unique mouse models, the quadruple Timp null strain (QT) as well as mice harboring only a single Timp3 allele (QT3 ). QT mice are grossly smaller and exhibit a dramatic reduction of trabeculae in long bones by μCT imaging with a corresponding increase in metalloproteinase activity. At the cellular level, Timp deficiency compromised differentiation markers, matrix deposition and mineralization in neonatal osteoblasts from calvariae, as well as the fibroblastic colony-forming unit (CFU-F) capacity of bone marrow-derived stromal cells. In contrast, we observed that osteoclasts were overactive in the Timp null state, consistent with the noted excessive bone resorption of QT bones. Immunohistochemistry (IHC) and immunofluorescence (IF) analyses of bone sections revealed higher Cathepsin K and RANKL signals upon Timp loss. Seeking the molecular mechanism, we identified abnormal TNFα bioactivity to be a central event in Timp-deficient mice. Specifically, TNFα triggered induction of the Wnt signaling inhibitor Dkk1 in the osteoblasts at the mRNA and protein levels, with a simultaneous increase in RANKL. Neutralizing TNFα antibody was capable of rescuing the induction of Dkk1 as well as RANKL. Therefore, the generation of novel Timp-deficient systems allowed us to uncover the essential and collective function of TIMP proteins in mammalian long-bone homeostasis. Moreover, our study discovers a functional TIMP/metalloproteinase-TNFα-Dkk1/RANKL nexus for optimal control of the bone microenvironment, which dictates coexistence of the osteoblast and osteoclast lineages. © 2018 American Society for Bone and Mineral Research.

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Deficiency and Also Transgenic Overexpression of Timp-3 Both Lead to Compromised Bone Mass and Architecture In Vivo

Cited by 17 publications

References 57 publications

Altered Bone Mechanics, Architecture and Composition in the Skeleton of TIMP-3-Deficient Mice

Altered Bone Mechanics, Architecture and Composition in the Skeleton of TIMP-3-Deficient Mice

Targeted Inhibition of Aggrecanases Prevents Articular Cartilage Degradation and Augments Bone Mass in the STR/Ort Mouse Model of Spontaneous Osteoarthritis

TIMP Loss Activates Metalloproteinase-TNFα-DKK1 Axis To Compromise Wnt Signaling and Bone Mass

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