Insights into Bone Morphogenetic Protein—(BMP-) Signaling in Ocular Lens Biology and Pathology

Abstract

Bone morphogenetic proteins (BMPs) are a diverse class of growth factors that belong to the transforming growth factor-beta (TGFβ) superfamily. Although originally discovered to possess osteogenic properties, BMPs have since been identified as critical regulators of many biological processes, including cell-fate determination, cell proliferation, differentiation and morphogenesis, throughout the body. In the ocular lens, BMPs are important in orchestrating fundamental developmental processes such as induction of lens morphogenesis, and specialized differentiation of its fiber cells. Moreover, BMPs have been reported to facilitate regeneration of the lens, as well as abrogate pathological processes such as TGFβ-induced epithelial-mesenchymal transition (EMT) and apoptosis. In this review, we summarize recent insights in this topic and discuss the complexities of BMP-signaling including the role of individual BMP ligands, receptors, extracellular antagonists and cross-talk between canonical and non-canonical BMP-signaling cascades in the lens. By understanding the molecular mechanisms underlying BMP activity, we can advance their potential therapeutic role in cataract prevention and lens regeneration.

Generation of Lens Progenitor Cells and Lentoid Bodies from Pluripotent Stem Cells: Novel Tools for Human Lens Development and Ocular Disease Etiology

“…The subsequent steps of individual cultures differ from no growth factors/drugs added, to single (e.g., BMP4, IGF-1, and SU5402) and multiple combinatorial treatments (e.g., BMP4, BMP7, and FGF2, see Figure 2 ). Although no procedure quantitatively analyzed parallel formation of lens cells and other cell types, their variable outcomes reflect the heterogeneity of the presumptive transitional populations of biased, specified, and determined cell types and their responses to activation of TGF-β/BMP [ 48 ] and activation or repression of FGF/MAPK [ 49 ] signal transduction pathways. We propose that variable expression of multiple individual BMP and TGFβ type 1 and type 2 receptors and FGFR1-4 dimers and their particular sensitivities to the growth factors and/or their antagonists or agonists present on the cell surface modulate the outcomes towards each desired cell type, i.e., adenohypophyseal, olfactory, and lens placodes, as well as more posterior otic placodes [ 167 ].…”

“…In addition, the posterior vitreous contains a lower concentration of oxygen compared to the anterior aqueous humor chamber [ 232 ]. Finally, it is well-established that normal lens development and postnatal growth are regulated predominantly by BMP, FGF/MAPK, and Wnt signaling pathways [ 28 , 46 , 48 , 49 , 233 ]. Evidence exists that individual growth factors and their receptors are not evenly expressed along the lens vesicle and optic cup [ 27 , 35 , 234 , 235 , 236 , 237 ].…”

“…Likewise, determining the individual roles of BPMs, FGFs, their receptors, and nuclear effectors of these signal transduction pathways requires additional studies [ 28 , 48 , 49 ]. Fluorescent reporter pluripotent stem cells can be engineered using targeted insertions into genes of particular interest, such as transcription and growth factors, to assure that the engineering does not disrupt their normal function.…”

“…At its anterior portion, the polarized lens vesicle is patterned by gradients of BMP, FGF, IGF, PDGF, and Wnt growth factors. Spatially regulated expression of these growth factor receptors [ 46 , 47 , 48 , 49 ] subsequently forms the monolayer of the epithelium. The posterior portion of the lens vesicle undergoes cell cycle-exit coupled differentiation regulated by complex interactions between BMP, FGF, and PDGF signaling [ 50 , 51 , 52 , 53 ] to generate the primary lens fiber cells.…”

Structural analysis of the interaction between human cytokine BMP-2 and the antagonist Noggin reveals molecular details of cell chondrogenesis inhibition

“…Since BMPs take part in many cellular mechanisms, the deregulation of their signaling pathways can lead to various dysfunctions, affecting, for example, the cardiovascular ( 6 ), central nervous ( 7 ), and osteoarticular systems ( 8 ). To date, nineteen members of the BMP family have been identified, which show homologous 3D structures and significant sequence identity ( 9 ). Thus, BMPs generally are homodimeric molecules ( 10 , 11 ), with an interchain disulphide bond holding the subunits together.…”