Tropomyosin isoforms localize to distinct microfilament populations in osteoclasts

McMichael, Brooke K.; Kotadiya, Preeyal; Singh, Tejdeep; Holliday, L. Shannon; Lee, Beth S.

doi:10.1016/j.bone.2006.04.031

Cited by 58 publications

(57 citation statements)

References 47 publications

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“…We found previously that Tm-4 was expressed at similar levels in fibroblasts, which generate focal adhesions and stress fibers, but not podosomes or sealing zones [12]. Other studies of Tm-4 levels in whole tissues showed that this isoform was expressed at relatively high levels in kidney, liver, lung, spleen, and stomach in addition to embryonic fibroblasts.…”

Section: Discussionmentioning

confidence: 71%

“…In both cases, this tropomyosin was found in the inner faces of these structures [12], and we propose that Tm-4 is likely to stabilize these actin filaments by regulating access of other proteins that may play roles in actin turnover. Our knockdown and overexpression studies are consistent with this hypothesis; lower Tm-4 levels result in thinning of sealing zones while overexpression resulted in thickened podosome filaments and thickened but disrupted actin structures in osteoclasts on bone.…”

Section: Discussionmentioning

confidence: 74%

“…We previously showed that tropomyosin 4 is abundant in osteoclast adhesion structures, namely on the inner face of both the podosomal F-actin core and the F-actin ring of polarized osteoclasts [12]. Based on these data, we hypothesized a role for Tm-4 in stabilizing both podosomal and sealing zone microfilaments.…”

Section: Suppression Of Tropomyosin 4 Levels Results In Thinning Of Tmentioning

confidence: 88%

“…Cells briefly were fixed in a solution of 1% formaldehyde in pH 6.5 stabilization buffer (127 mM NaCl, 5 mM KCl, 1.1 mM NaH 2 PO 4 , 0.4 mM KH 2 PO 4 , 2 mM MgCl 2 , 5.5 mM glucose, 1 mM EGTA, 20 mM Pipes), and subsequently were more extensively fixed and permeabilized in a solution of 2% formaldehyde, 0.2% Triton X-100, and 0.5% deoxycholate in the same stabilization buffer [12,17]. Primary antibodies were added in a standard blocking buffer, and were detected using Alexa-labeled secondary antibodies (Invitrogen Corp., Carlsbad, CA).…”

Section: Immunocytochemistry and Microscopymentioning

confidence: 99%

“…Approximately forty isoforms of tropomyosins now have been identified in rodents, and most of these are expressed in nonmuscle cells [11]. We showed recently that at least seven isoforms are present in osteoclasts, and that one of these isoforms, tropomyosin 4 (Tm-4), was distributed both in the core of podosomes, and on the inner face of sealing zones [12]. Thus, Tm-4 appears to be a prime candidate for regulating osteoclast attachment and bone resorptive capacity.…”

Section: Introductionmentioning

confidence: 99%

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Tropomyosin 4 regulates adhesion structures and resorptive capacity in osteoclasts

McMichael

Lee

2008

Experimental Cell Research

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Tropomyosins (Tms) are α-helical dimers that bind and stabilize actin microfilaments while regulating their accessibility to other actin-associated proteins. Four genes encode expression of over forty Tms, most of which are expressed in nonmuscle cells. In recent years, it has become clear that individual Tm isoforms may regulate specific actin pools within cells. In this study, we examined how osteoclast function may be regulated by the tropomyosin isoform Tm-4, which we previously showed to be highly localized to podosomes and sealing zones of osteoclasts. RNAi-mediated knockdown of Tm-4, both in RAW264.7-and mouse marrow-derived osteoclasts, resulted in thinning of the actin ring of the sealing zone. Knockdown of Tm-4 also resulted in diminished bone resorptive capacity and altered resorption pit shape. In contrast, osteoclasts overexpressing Tm-4 demonstrated thickened podosomes on glass as well as thickened, aberrant actin structures on bone, and diminished motility and resorptive capacity. These results indicate that Tm-4 plays a role in regulating adhesion structures of osteoclasts, most likely by stabilizing the actin microfilaments present in podosomes and the sealing zone.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 74%

Section: Suppression Of Tropomyosin 4 Levels Results In Thinning Of Tmentioning

confidence: 88%

Section: Immunocytochemistry and Microscopymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tropomyosin 4 regulates adhesion structures and resorptive capacity in osteoclasts

McMichael

Lee

2008

Experimental Cell Research

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Tropomyosin 4 defines novel filaments in skeletal muscle associated with muscle remodelling/regeneration in normal and diseased muscle

Vlahovich

Schevzov

Nair-Shaliker

et al. 2007

Cell Motil. Cytoskeleton

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The organisation of structural proteins in muscle into highly ordered sarcomeres occurs during development, regeneration and focal repair of skeletal muscle fibers. The involvement of cytoskeletal proteins in this process has been documented, with nonmuscle gamma-actin found to play a role in sarcomere assembly during muscle differentiation and also shown to be up-regulated in dystrophic muscles which undergo regeneration and repair [Lloyd et al.,2004; Hanft et al.,2006]. Here, we show that a cytoskeletal tropomyosin (Tm), Tm4, defines actin filaments in two novel compartments in muscle fibers: a Z-line associated cytoskeleton (Z-LAC), similar to a structure we have reported previously [Kee et al.,2004], and longitudinal filaments that are orientated parallel to the sarcomeric apparatus, present during myofiber growth and repair/regeneration. Tm4 is upregulated in paradigms of muscle repair including induced regeneration and focal repair and in muscle diseases with repair/regeneration features, muscular dystrophy and nemaline myopathy. Longitudinal Tm4-defined filaments also are present in diseased muscle. Transition of the Tm4-defined filaments from a longitudinal to a Z-LAC orientation is observed during the course of muscle regeneration. This Tm4-defined cytoskeleton is a marker of growth and repair/regeneration in response to injury, disease state and stress in skeletal muscle.

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A cytoskeletal tropomyosin can compromise the structural integrity of skeletal muscle

Kee

Gunning

Hardeman

2009

Cell Motil. Cytoskeleton

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We have identified a number of extra-sarcomeric actin filaments defined by cytoskeletal tropomyosin (Tm) isoforms. Expression of a cytoskeletal Tm (Tm3) not normally present in skeletal muscle in a transgenic mouse resulted in muscular dystrophy. In the present report we show that muscle pathology in this mouse is late onset (between 2 and 6 months of age) and is predominately in the back and paraspinal muscles. In the Tm3 mice, Evans blue dye uptake in muscle and serum levels of creatine kinase were markedly increased following downhill exercise, and the force drop following a series of lengthening contractions in isolated muscles (extensor digitorum longus) was also significantly increased in these mice. These results demonstrate that expression of an inappropriate Tm in skeletal muscle results in increased susceptibility to contraction-induced damage. The extra-sarcomeric actin cytoskeleton therefore may have an important role in protecting the muscle from contractile stress.

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Tropomyosin isoforms localize to distinct microfilament populations in osteoclasts

Cited by 58 publications

References 47 publications

Tropomyosin 4 regulates adhesion structures and resorptive capacity in osteoclasts

Tropomyosin 4 regulates adhesion structures and resorptive capacity in osteoclasts

Tropomyosin 4 defines novel filaments in skeletal muscle associated with muscle remodelling/regeneration in normal and diseased muscle

A cytoskeletal tropomyosin can compromise the structural integrity of skeletal muscle

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