Myeloma Bone Disease: The Osteoblast in the Spotlight
Abstract
:1. Introduction
2. Pathophysiology of Myeloma Bone Disease
3. Osteoblast Dysfunction
4. Osteoblast Inhibiting Factors
4.1. Wnt/B-Catenin; DKK1, Frizzled Transmembrane Receptors and Sclerostin
4.2. TGFβ, ACTIVIN A, BMPs, and HGF
4.3. Interleukins
4.4. Other Factors
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
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OIFs | Expressed/Released by | Action | References |
---|---|---|---|
Activin A | OBs | Inhibits OB differentiation via SMAD2 | [11,12,13] |
Dkk-1 | OB, BMSCs, and MPCs | Inhibits Wnt/β-catenin via LRP5/6 binding, increases osteoclastogenesis by reducing OPG | [14,15,16] |
Gfi1 | BMSC | Inhibits Runx2 expression | [17] |
HGF | MPCs | Inhibits BMP signalling | [18,19] |
HPSE | MPCs | Increases DKK1 (to inhibit Wnt signalling) and inhibits Runx2 expression | [20] |
IL-3 | BM T cells | Inhibits BMP-2 initiated OB differentiation | [21,22] |
IL-7 | BM T cells in MM | Decreases Runx2/Cbfa1 activity, inhibits OB differentiation/maturation | [23,24,25] |
IL-11 | Likely BMSCs | Dual role as OIF and OAF | [26] |
MIP-1α (CCL3) | MPCs and macrophages | Inhibits Runx2 and downregulates Osterix | [27,28] |
N-cadherin | MPCs | Over expressed in 50% MM patients, inhibits OB differentiation via inhibited Wnt signalling | [29] |
PIM2 | MPCs, MBSCs, and pre-OBs | Associated with reduced OB function, possibly via BMP2 | [30] |
Sclerostin | MPCs and OCYs | Inhibits Wnt/β-catenin via LRP5/6 binding, leading to inhibited osteoblastogenesis | [14,31,32] |
sFRP-2 | MPCs | Inhibits Wnt/β-catenin by altering Wnt/Frizzled binding (decoy receptor), inhibits BMP-2 induced OB differentiation | [33] |
sFRP-3 | MPCs | Inhibits OB differentiation via BMP-2 | [33] |
TNF-α | MPCs | Increases rates of mature OB apoptosis, possible due to interactions with Runx2 | [34,35] |
TGFβ | Bone matrix | Inhibits OB differentiation via Runx and DLX-5 | [36] |
Pharmaceutical Agents | Development Status | Mechanism | Action |
---|---|---|---|
Nitrogen-containing bisphosphonates (e.g., Zoledronate) | Approved in MBD | Inhibit farnesyl diphosphate synthase | Inhibit OCs |
Non-nitrogen-containing bisphosphonates (e.g., Clodronate) | Approved in MBD | Inhibit ATP-dependent enzymes | Inhibit OCs |
Denosumab | Approved in MBD | Anti-RANKL monoclonal antibody | Inhibit OCs |
Romosozumab | Approved in OP, preclinical investigation in MBD | Anti-sclerostin monoclonal antibody | Promote OBs |
Sotatercept | Phase IIa clinical trial in MBD | Recombinant activin type IIa receptor ligand trap | Promote OBs |
BHQ880 | Phase Ia and II clinical trials in MBD | Anti-Dkk-1 neutralising antibody | Promote OBs |
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Andrews, R.E.; Brown, J.E.; Lawson, M.A.; Chantry, A.D. Myeloma Bone Disease: The Osteoblast in the Spotlight. J. Clin. Med. 2021, 10, 3973. https://doi.org/10.3390/jcm10173973
Andrews RE, Brown JE, Lawson MA, Chantry AD. Myeloma Bone Disease: The Osteoblast in the Spotlight. Journal of Clinical Medicine. 2021; 10(17):3973. https://doi.org/10.3390/jcm10173973
Chicago/Turabian StyleAndrews, Rebecca E., Janet E. Brown, Michelle A. Lawson, and Andrew D. Chantry. 2021. "Myeloma Bone Disease: The Osteoblast in the Spotlight" Journal of Clinical Medicine 10, no. 17: 3973. https://doi.org/10.3390/jcm10173973
APA StyleAndrews, R. E., Brown, J. E., Lawson, M. A., & Chantry, A. D. (2021). Myeloma Bone Disease: The Osteoblast in the Spotlight. Journal of Clinical Medicine, 10(17), 3973. https://doi.org/10.3390/jcm10173973