LRP5, Bone Mass Polymorphisms and Skeletal Disorders

Abstract

The formation and maintenance of the gross structure and microarchitecture of the human skeleton require the concerted functioning of a plethora of morphogenic signaling processes. Through recent discoveries in the field of genetics, numerous genotypic variants have been implicated in pathologic skeletal phenotypes and disorders arising from the disturbance of one or more of these processes. For example, total loss-of-function variants of LRP5 were found to be the cause of osteoporosis-pseudoglioma syndrome (OPPG). LRP5 encodes for the low-density lipoprotein receptor-related protein 5, a co-receptor in the canonical WNT-β-catenin signaling pathway and a crucial protein involved in the formation and maintenance of homeostasis of the human skeleton. Beyond OPPG, other partial loss-of-function variants of LRP5 have been found to be associated with other low bone mass phenotypes and disorders, while LRP5 gain-of-function variants have been implicated in high bone mass phenotypes. This review introduces the roles that LRP5 plays in skeletal morphogenesis and discusses some of the structural consequences that result from abnormalities in LRP5. A greater understanding of how the LRP5 receptor functions in bone and other body tissues could provide insights into a variety of pathologies and their potential treatments, from osteoporosis and a variety of skeletal abnormalities to congenital disorders that can lead to lifelong disabilities.

Keywords: LRP5; OPPG; high bone mass; low bone mass; low-density lipoprotein receptor-related protein 5; osteoporosis-pseudoglioma syndrome; skeletal dysmorphogenesis; skeletal phenotype.

Figure 1

Radiological findings in four patients with OPPG. Multiple fractures and deformities at a young age are typical in OPPG. (A) Patient with mid-shaft fractures of the right radius and ulna. (B) The same patient displaying an approximately 90-degree angulation deformity in the mid-femoral diaphysis with co-existing deformity of the distal metaphysis. (C) Another patient displaying coxa valga and a varus angulated fracture at the distal femoral metaphysis. (D) A patient displaying bilateral coxa vara and lytic proximal femora, with disorganized tensile and compressive trabeculae and diaphyseal sclerosis. (E) Another patient in bilateral lower extremity casts secondary to bilateral femur fractures exhibiting coxa valga, very thin long bones, and bowing of the femora. Adapted with permission from Ref. [39]. 2022, Osteoporosis International.

Figure 2

Radiographic findings in a 10-year-old female with FEVR. (A,B) Anteroposterior view of the left humerus (A) and right forearm (B) exhibiting gracile bones and thin cortices. (C) Anteroposterior view of the tibias revealing endosteal reabsorption with widened medullary canals and thin cortices characteristic of osteoporosis. (D) Panorex film displaying impaired dentinogenesis manifested by the absence of the maxillary right and left lateral incisors, maxillary right and left 2nd pre-molars, and right mandibular 1st pre-molar. Adapted with permission from Ref. [51]. 2023. Orthopedic Research and Reviews 2023:15 39-45. Originally published by and used with permission from Dove Medical Press Ltd., Macclesfield, England.

Figure 3

(A) Lateral and (B) anteroposterior radiographs of the right forearm of a patient with LRP5 variant-induced familial exudative vitreoretinopathy (FEVR) showing radial and ulnar fractures (black arrows). Angulation is noted on the lateral X-ray (white arrow) suggesting possible instability and loss of physiological position.

Figure 4

Anteroposterior radiograph of right radial and ulnar fractures of a patient with LRP5 variant-induced familial exudative vitreoretinopathy (FEVR). The fractures, which were initially undisplaced (Figure 3), became angulated, encroaching upon the interosseous space and potentially limiting supination and pronation. Preservation of rotational motion of the forearm was achieved by intramedullary rodding of the radius, restoring physiological alignment. Fracture callus is seen at the ulnar fracture (white arrow). Due to the young age of the patient, the residual angulation of the ulna underwent remodeling to a physiological position.

Figure 5

Radiographs of the upper extremity (A), lower extremity (B), pelvis (C), and spine (D) in a 31-year-old female with a gain-of-function variant in LRP5. Sclerosis can be seen in the vertebrae, the pelvic bones, the sacrum, and the cortices of the long bones, with corresponding narrowing of the medullary canals. Adapted with permission from Ref. [54]. 2005, Journal of Bone and Mineral Research.

Figure 6

Cranial radiographs of a patient with a gain-of-function missense variant in LRP5 taken at 1 year and 10 months of age (A) and at 3 years and 5 months of age (B). Progressive sclerosis of the cranial base and vault can be observed, and a craniotomy was performed at 11 months of age as a treatment for craniosynostosis. Adapted with permission from Ref. [54]. 2005, Journal of Bone and Mineral Research.