Two Modulators of Skeletal Development: BMPs and Proteoglycans

Abstract

During embryogenesis, skeletal development is tightly regulated by locally secreted growth factors that interact with proteoglycans (PGs) in the extracellular matrix (ECM). Bone morphogenetic proteins (BMPs) are multifunctional growth factors that play critical roles in cartilage maturation and bone formation. BMP signals are transduced from plasma membrane receptors to the nucleus through both canonical Smad and noncanonical p38 mitogen-activated protein kinase (MAPK) pathways. BMP signalling is modulated by a variety of endogenous and exogenous molecular mechanisms at different spatiotemporal levels and in both positive and negative manners. As an endogenous example, BMPs undergo extracellular regulation by PGs, which generally regulate the efficiency of ligand-receptor binding. BMP signalling can also be exogenously perturbed by a group of small molecule antagonists, such as dorsomorphin and its derivatives, that selectively bind to and inhibit the intracellular kinase domain of BMP type I receptors. In this review, we present a current understanding of BMPs and PGs functions in cartilage maturation and osteoblast differentiation, highlighting BMP–PG interactions. We also discuss the identification of highly selective small-molecule BMP receptor type I inhibitors. This review aims to shed light on the importance of BMP signalling and PGs in cartilage maturation and bone formation.

Could BMPs Therapy Be Improved if BMPs Were Used in Composition Acting during Bone Formation in Endochondral Ossification?

“…The transforming growth factor beta (TGFβ) superfamily contains more than 30 members, including TGFβs, bone morphogenetic proteins (BMPs), growth differentiation factors (GDFs), and activins, that work through a wide variety of signalling pathways, i.e., through different ligands, receptors and signalling molecules [ 7 , 20 , 21 , 22 , 23 , 24 ]. The name BMP refers to molecules that evoke the activation of the canonical BMP signalling pathway, restricting the list to approximately 15 BMP ligands in humans [ 9 , 23 ]. Ligands from the BMP family can form homodimeric or heterodimeric complexes, except BMP3 and BMP15, which work as monomers.…”

“…Moreover, the ability to induce bone formation and the signalling action of homodimers BMP2, BMP4, BMP5, BMP6, and BMP7 increases up to 50 times when they act in heteromeric forms, such as BMP2/5, BMP2/6, BMP2/7, and BMP4/7. This mechanism is associated with the higher affinity of BMP receptors to BMP heterodimers [ 9 ]. Bone morphogenetic protein receptors (BMPRs) are transmembrane, receptors with the activity of serine-threonine kinase divided into type I and II.…”

“…In the canonical pathway, activated type I receptors phosphorylate and activate Smad1, 5, and 8 (R-Smad) recruit co-Smad (Smad4) to form heteromeric complexes. Then, such complexes are transported into the nucleus and recruit transcription factors, e.g., Hox-C8 (homeobox protein C8), and RUNX2 (runt-related transcription factor 2) and regulate the expression of significant osteogenic genes [ 9 , 10 ]. Smad proteins (homologues of the Drosophila protein, mothers against decapentaplegic (Mad) and the Caenorhabditis elegans protein Sma) include R-Smads (receptor-regulated Smads), i.e., Smad1, Smad5 and Smad8 [ 7 ] and Smad4 (Co-Smad common partner Smad).…”

“…In the non-canonical pathway, activated type I receptors phosphorylate MAP3K7 (mitogen-activated protein kinase kinase kinase 7 or TAK1—TGFβ-activated kinase 1) recruit MAP3K7IP1 (MAP3K-interacting protein 1 or TAB1—TAK1 binding protein 1) and initiates a p38 MAPK signalling cascade. The phosphorylated form of p38 MAPK phosphorylates and activates RUNX2, DLX-5 (distal-less homeobox 5), and Sp7 or Osx (specificity protein 7 or osterix) transcription factors to evoke the expression of osteogenic genes [ 9 , 10 ]. For example, activation of the MAPK-Smad2/3 pathway by TGFβ can stimulate osteoprogenitor proliferation and osteoblastic lineage formation.…”

“…The isolation of bone morphogenetic proteins from bovine material and the production of their human equivalents by genetic engineering inspired hope that their application would considerably improve the treatment of bone disorders [ 1 ]. BMPs and other growth factors act on mesenchymal stem cells (MSCs), stimulating their differentiation into osteoprogenitor cells, as well as the differentiation of the latter into osteoblasts and osteoclasts [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ]; thus, they were obvious candidates for clinical use. Unfortunately, their application in numerous instances was disappointing and caused various harmful side effects [ 15 ].…”