Exploring the Role of Urocortin in Osteoporosis

Abstract

Osteoporosis is a debilitating disease that affects over 200 million people worldwide. Overactive osteoclast activity leads to micro-architectural defects and low bone mass. This culminates in fragility fractures, such as femoral neck fractures. Treatments currently available either are not completely effective or have considerable side effects; thus, there is a need for more effective treatments. The urocortin (Ucn) family, composed of urocortin 1 (Ucn1), urocortin 2 (Ucn2), urocortin 3 (Ucn3), corticotropin-releasing factor (CRF) and corticotropin-releasing factor-binding protein (CRF-BP), exerts a wide range of effects throughout the body. Ucn1 has been shown to inhibit murine osteoclast activity. This review article will aim to bridge the gap between existing knowledge of Ucn and whether it can affect human osteoclasts.

Keywords: osteoclast; osteoporosis; treatment choices; urocortin; urocortin 1.

Figure 1. Most frequent locations where osteoporotic fractures occur.

Circles highlight the locations of the most susceptible bones. Darker circles indicate higher economic cost to the state (in descending order: the femoral neck, vertebra, forearm and pelvis). Adapted from Hernlund et al. [3] and Skeletons and Bones [12] with permission

Figure 2. Cross-section of the bone.

Overview of the cross-section of the bone, adapted from Skeletons and Bones [12] and Clarke [17] with permission

Figure 3. Summary of the mechanism of bone resorption.

RANKL is expressed by osteoblasts, which binds to RANK receptors expressed by the osteoclast, stimulating formation and function as described earlier. The villous projections of the osteoclast form a ruffled border around the bone area to be absorbed. This is aided by podosomes and osteopontin (an associated link protein), which form an adhesive ring around the ruffled border. The result is an isolated resorptive pit. CO₂ and H₂O form carbonic acid, which dissociates into an H+ cation and a bicarbonate ion (HCO₃-). The H+ is substituted for a chloride ion (Cl-). H+ and Cl- form hydrochloric acid, which breaks down the bone. Furthermore, lysosomal enzymes are also secreted by the osteoclast to further break down the bone. The resorptive pit is shielded from extracellular fluid and other environmental stimuli, to ensure an acidic, resorptive environment. Taken from Asagiri and Takayanagi [35] and Calcium homeostasis and osteoporosis [36] with permission RANKL, receptor activator of nuclear factor kappa-B ligand; RANK, receptor activator of nuclear factor kappa; OPG, osteoprotegerin

Figure 4. A summary of the pathophysiology in osteoporosis.

Image credit: OM Ismail IL-1, interleukin 1; IL-6, interleukin 6; TNF-α, tumour necrosis factor-alpha; RANK, receptor activator of nuclear factor kappa

Figure 5. A comparison of the primary structure of the human Ucn/CRF family peptides.

The boxed regions represent the amino acid sequence. The black fill represents CRF superfamily homology (five residues). The blue fill indicates selective type 1 Ucn1/CRF homology (six residues). The green fill indicates selective type 2 Ucn homology (four residues). The red fill indicates pan-Ucn homology (three residues). This demonstrates how CRF and Ucn1 are structurally similar and how Ucn2 and Ucn3 are structurally similar: ‘type 1 (Ucn1/CRF)’ versus ‘type 2 (Ucn2/Ucn3)’. Adapted from Fekete and Zorrilla [60] with permission Ucn, urocortin; Ucn1, urocortin 1; Ucn2, urocortin 2; Ucn3, urocortin 3; CRF, corticotropin-releasing factor

Figure 6. A summary of the affinity of CRF and each Ucn paralog to bind to each CRF-binding site.

The dashed line represents a relatively low binding affinity. Adapted from Giardino and Ryabinin [75] with permission CRF, corticotropin-releasing factor; CRF1, CRF receptor 1; CRF2, CRF receptor 2; CRF-BP, CRF-binding protein; Ucn1, urocortin 1; Ucn2, urocortin 2; Ucn3, urocortin 3