Extracellular Microfibrils Control Osteoblast-supported Osteoclastogenesis by Restricting TGFβ Stimulation of RANKL Production

Abstract

Mutations in fibrillin-1 or fibrillin-2, the major structural components of extracellular microfibrils, cause pleiotropic manifestations in Marfan syndrome and congenital contractural arachnodactyly, respectively. We recently found that fibrillin-1 and fibrillin-2 control bone formation by regulating osteoblast differentiation through the differential modulation of endogenous TGF␤ Fibrillins are ubiquitous extracellular matrix (ECM) 2 glycoproteins that impart key physical properties to connective tissues and that control the local bioavailability of transforming growth factor-␤ (TGF␤) family members (1). The structural role of fibrillins is exerted through the temporal and hierarchical formation of tissue-specific assemblies (microfibrils and elastic fibers), whereas the instructive role reflects the ability of these extracellular molecules to bind TGF␤ and bone morphogenetic protein (BMP) complexes (1). Fibrillin monomers selfassemble into microfibrils that associate or interact with several other matrix proteins, including fibulins, microfibril-associated glycoproteins (MAGPs), and latent TGF␤-binding proteins, as well as with elastin in the elastic fibers (2, 3). Binding of latent TGF␤-binding proteins to fibrillin and fibronectin assemblies indirectly targets latent TGF␤ complexes to the ECM (4 -6). Likewise, sequestration of BMPs in the matrix is mediated in part by direct interaction of their prodomains with the N-terminal regions of fibrillins (7).Mutations of fibrillin genes in human patients and genetically engineered mice have been correlated with discrete phenotypic outcomes that reflect the dual roles of microfibrils in tissue formation, integrity, and remodeling (8). Like patients afflicted with Marfan syndrome (MFS; OMIM-154700), mice harboring mutations that affect the structure or synthesis of fibrillin-1 display dissecting aortic aneurysm, mitral valve prolapse, muscle hypoplasia, and developmental emphysema (9 -11). These manifestations are in part accounted for by promiscuous Smad2/3 signaling secondary to improper ECM sequestration of latent TGF␤ complexes (10, 12, 13). Fbn2Ϫ/Ϫ mice, on the other hand, recapitulate the small and large joint contractures that are the hallmark of individuals affected with congenital contractural arachnodactyly (CCA; OMIM-121050), a disease akin to but clinically distinct from MFS (14, 15). Fbn2 Ϫ/Ϫ mice also display a skeletal patterning defect (syndactyly) that is absent in Fbn1 Ϫ/Ϫ mice and that was genetically linked with decreased BMP7 signaling in the mesenchyme of early autopods (14, 16). Neither the relative patterns of fibrillin gene expression in various tissues, including the forming and mature skeleton, nor the established contributions of fibrillin proteins to microfibril biogenesis can fully account for the discrete phenotypic outcomes in MFS and CCA and their respective mouse models (2, 3). Hence, there is a need to explain how fibrillin-1 and fibrillin-2 contribute differently to the structural properties of extracellular microfibrils and thei...

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

“…Although the TGF-b bioavailability in skeletal tissue of MFS patients has not been evaluated, TGF-b ligands are abundantly expressed in growth plates and bone (Pedrozo et al 1998;Minina et al 2005). Osteoblasts derived from fibrillin (Fbn1 or Fbn2)-deficient mice show abnormal activation of TGF-b signaling (Nistala et al 2010). The stimulatory effect of TGF-b on cell proliferation and chondrogenesis in the growth plate and its inhibition of chondrocyte maturation suggest that bone overgrowth in MFS may result from growth plate enlargement.…”

“…For example, fibrillin has been shown by surface plasmon resonance to bind BMP-2, BMP-4, BMP-7, BMP-10, and GDF-5 (Sengle et al 2008). In particular, the interaction between fibrillin-1 and BMP-4 has been shown to be important for regulating BMP-4 bioavailability (Nistala et al 2010). Although latent TGF-b can also be found in association with glycoprotein-A repetitions predominant protein (GARP) (Stockis et al 2009;Wang et al 2012), expression of GARP appears to be limited to platelets and regulatory T lymphocytes (Macaulay et al 2007;Tran et al 2009), suggesting that this regulatory molecule is not a major regulator of TGF-b bioavailability in the ECM (Stockis et al 2009;Tran et al 2009;Wang et al 2012).…”

“…The stimulatory effect of TGF-b on cell proliferation and chondrogenesis in the growth plate and its inhibition of chondrocyte maturation suggest that bone overgrowth in MFS may result from growth plate enlargement. In addition to perturbed TGF-b bioavailability, MFS mutations might also alter binding of fibrillin-1 to BMPs (Arteaga-Solis et al 2001;Sengle et al 2008;Nistala et al 2010), suggesting that skeletal abnormalities in MFS might result from altered, and perhaps misbalanced, BMP and TGF-b signaling.…”

E-selectin ligand 1 regulates bone remodeling by limiting bioactive TGF-β in the bone microenvironment

“…For example, excessive TGF-β bioavailability in the bone of Fibrillin 2 knockout (Fbn2 −/− ) mice significantly elevates OBderived RANKL level and leads to osteoporosis (31). In our previous studies, we identified that PTHrP, a TGF-β downstream target, is significantly up-regulated in Esl-1 −/− cartilage and accounts for the shortening of the growth plate (19).…”

Fibrillin-containing microfibrils are key signal relay stations for cell function

“…TGF-β1 stimulates matrix degradation through the induction of osteoclastogenesis (Nistala et al 2010b). BMPs have an osteoinductive effect during bone maturation, mineralization and homeostasis.…”