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Inflammatory bone loss: pathogenesis and therapeutic intervention

Key Points

  • Bone homeostasis is dependent on the concerted actions of bone-building osteoblasts and bone-degrading osteoclasts — a process called bone remodelling.

  • Two of the major factors that induce osteoblast differentiation and activation are: the signalling mediated by bone morphogenetic proteins via runt-related transcription factor 2; and the WNT–Frizzled–β-catenin pathway. Conversely, Dickkopf-related protein 1 (DKK1) and sclerostin inhibit osteoblast activation.

  • Major molecules involved in osteoclast differentiation and activation include macrophage colony-stimulating factor and receptor activator of nuclear factor-κB (RANK) as well as its ligand (RANKL).

  • Inflammation is associated with the overproduction of various cytokines, such as tumour necrosis factor, interleukin-1 (IL-1), IL-6 or IL-17. Their upregulation in the course of inflammation leads to excessive bone degradation mainly due to hyperactivation of osteoclasts, although some cytokines can also impair osteoblast function.

  • Many diseases lead to inflammatory bone loss, including inflammatory bowel disease, chronic obstructive lung disease, cystic fibrosis, periodontitis, rheumatoid arthritis and other inflammatory diseases.

  • Inflammatory bone loss is always systemic, and in some diseases — such as rheumatoid arthritis or periodontitis — it can also involve local bone.

  • Therapies interfering with inflammation also affect systemic inflammatory bone loss, primarily by reducing the effects of cytokines on osteoclast activation; however, many of these treatments will not fully control inflammation. Owing to this ongoing inflammatory activity (even at low levels), bone loss will continue to accrue and therefore also requires specific targeting of bone cells.

  • Bisphosphonates and denosumab are among the bone-targeting therapies that have been shown to be effective in treating inflammatory bone loss, but it is assumed that blockers of DKK1 and sclerostin — which are upregulated by cytokines and inhibit osteoblast repair mechanisms — are also likely to be effective.

Abstract

Bone is a tissue undergoing continuous building and degradation. This remodelling is a tightly regulated process that can be disturbed by many factors, particularly hormonal changes. Chronic inflammation can also perturb bone metabolism and promote increased bone loss. Inflammatory diseases can arise all over the body, including in the musculoskeletal system (for example, rheumatoid arthritis), the intestine (for example, inflammatory bowel disease), the oral cavity (for example, periodontitis) and the lung (for example, cystic fibrosis). Wherever inflammatory diseases occur, systemic effects on bone will ensue, as well as increased fracture risk. Here, we discuss the cellular and signalling pathways underlying, and strategies for therapeutically interfering with, the inflammatory loss of bone.

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Figure 1: Maintenance of bone structure.
Figure 2: Signalling in osteoblasts in health and during inflammation.
Figure 3: Signalling in osteoclasts in health and during inflammation.
Figure 4: Summary of local and systemic bone events in chronic inflammation, and therapeutic options.

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Acknowledgements

The authors would like to thank B. Niederreiter for expert support.

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Correspondence to Kurt Redlich or Josef S. Smolen.

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Competing interests

Josef Smolen has received grant support and/or speaking or consulting fees from Abbott, Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Lilly, Merck Sharp & Dohme, Pfizer, Roche, Sandoz and UCB Pharma, and has been a principal investigator in clinical trials at Abbott, Janssen, Pfizer, Roche, Sandoz and UCB Pharma.

Kurt Redlich has received grant support and/or speaking or consulting fees from Abbott, Bristol-Myers Squibb, Amgen, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Pfizer, Roche and UCB Pharma.

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Amgen website — 21 April 2011 press release

Glossary

Receptor activator of NF-κB ligand

(RANKL). The ligand for receptor activator of NF-κB (RANK). RANKL is expressed on osteoblasts and other mesenchymal cells, as well as on non-mesenchymal cells such as T- and B lymphocytes. It is also secreted as a soluble molecule. Furthermore, mesenchymal cells can produce osteoprotegerin, which is a decoy receptor of RANKL that prevents the binding of RANKL to RANK. A monoclonal antibody against RANKL, denosumab, is licensed for the treatment of osteoporosis.

Glycoprotein 130

(gp130). A transmembrane protein forming the signalling subunit of the interleukin-6 (IL-6) receptor family. When IL-6 or other IL-6 family members bind to their specific receptors (α-chain), they can interact with the gp130 protein (β-chain). Subsequently, this triplet dimerizes to form a hexamer. The gp130 co-receptor activates signal transduction via Janus kinases.

Sclerosteosis

A rare, hereditary bone disease in which bones grow abnormally to produce a high bone mass phenotype; it is due to mutations in the gene encoding sclerostin, which is produced primarily by osteocytes and inhibits osteoblast function.

Receptor activator of NF-κB

(RANK). A transmembrane protein belonging to the tumour necrosis factor receptor family and expressed on the surface of cells of haematopoietic origin. RANK is the pivotal cytokine receptor for osteoclastogenesis and leads to the activation of the transcription factor activator protein 1, which involves mainly heterodimers of the JUN and FOS families of proteins.

MicroRNAs

(miRNAs). Short ribonucleic acid molecules that comprise about 22 nucleotides; they bind to complementary sequences of mRNA molecules, leading to translational repression or degradation of the mRNA. Cellular functions can be inhibited or activated by miRNAs.

T helper 17

(TH17). A recently recognized, unique T helper (TH) cell subset that distinguishes itself from the traditional TH1 and TH2 subsets by producing interleukin-17 (IL-17). TH17 cells appear to have a pivotal role in the pathogenesis of chronic inflammatory and autoimmune diseases, and IL-17 is a strong inducer of RANKL and can thus activate osteoclastogenesis.

Bone mineral density

(BMD). An estimate of the amount of mineral matter, expressed as g per cm2 of bone. Its extent is expressed as a t-score (the number of standard deviations above or below the mean of gender- and ethnicity-matched healthy adults of 30 years of age) and z-score (the same as above but matched for the same age). A t-score lower than −2.5 standard deviations reflects osteoporosis.

Proteasome

A very large intracellular protein complex that enzymatically degrades damaged proteins but is also involved in the regulation of intracellular proteins. Proteasomes degrade bone morphogenetic proteins (BMPs), and proteasome inhibitors may therefore enhance the ability of BMPs to activate osteoblasts.

Exostoses

Bony overgrowths on a bony surface, frequently seen as spurs. This abnormal or exaggerated bone formation can occur in the context of an inflammatory response that involves bone, and may cause pain or discomfort.

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Redlich, K., Smolen, J. Inflammatory bone loss: pathogenesis and therapeutic intervention. Nat Rev Drug Discov 11, 234–250 (2012). https://doi.org/10.1038/nrd3669

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