Bone morphogenetic proteins: Their role in regulating osteoclast differentiation

Abstract

The ability to create recombinant bone morphogenetic proteins (BMPs) in recent years has led to their rise as a common clinical adjuvant. Their application varies, from spinal fixation to repairing palatal clefts, to coating implants for osseointegration. In recent years questions have been raised as to the efficacy of BMPs in several of these procedures. These questions are due to the unwanted side effect of BMPs on other cell types, such as osteoclasts which can resorb bone at the graft/implant site. However, most BMP research focuses on the anabolic osteoinductive effects of BMPs on osteoblasts rather than its counterpart- stimulation of the osteoclasts, which are cells responsible for resorbing bone. In this review, we discuss the data available from multiple in-vitro and in-vivo BMP-related knockout models to elucidate the different functions BMPs have on osteoclast differentiation and activity.

Keywords: BMP; Coupling; MAPK; Osteoclasts; Receptors; SMAD1/5.

Fig. 1

Osteoclast differentiation. Drawing depicts osteoclast differentiation and proteins involved in commitment, fusion and activity. Names of proteins under each heading are involved in the process described by the heading but does not indicate time of expression during osteoclast differentiation. Proteins involved in BMP signaling are highlighted in pink and based on data presented in Jensen et al. (2010) and Rodriguez et al. (2009). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Intersection of BMP and RANKL signaling pathways. Cartoon depicts downstream proteins activated by BMP and/or RANKL signaling pathways. Both pathways are able to activate TAK1 kinase which allows for activation of MAP kinase, SMAD1/5 and NF-kB (Qi et al., 2014).

Fig. 3

Role of BMPs in regulating osteoclast differentiation. “Up” arrows indicate that BMP2 positively regulates osteoclast proliferation and RANKL expression. Loss of BMPR-2 or BMPR-1 in myeloid cells leads to loss of osteoclast differentiation. TWSG1, Noggin or SMAD4 expression leads to inhibition of osteoclast differentiation. Lastly BMPR-1A and SMAD1/5 have been shown in mature osteoclasts to regulate osteoclast-osteoblast coupling signals.

Fig. 4

BMP signaling regulates osteoclast-osteoblast coupling. Osteoclasts secrete BMPs such as BMP6 or other factors such as Wnts regulated by BMP signaling to activate pre-osteoblasts' differentiation or bone formation by mature osteoblasts. During bone resorption osteoclasts release BMPs stored in the bone matrix. BMP signaling has also been shown to regulate expression of CX43/GJA1 in osteoclasts which interacts with osteoblast to regulate mineralization (Shi et al., 2017).