Abnormal Bone Collagen Cross‐Linking in Osteogenesis Imperfecta/Bruck Syndrome Caused by Compound Heterozygous PLOD2 Mutations

Abstract

Bruck syndrome (BS) is a congenital disorder characterized by joint flexion contractures, skeletal dysplasia, and increased bone fragility, which overlaps clinically with osteogenesis imperfecta (OI). On a genetic level, BS is caused by biallelic mutations in either FKBP10 or PLOD2 . PLOD2 encodes the lysyl hydroxylase 2 (LH2) enzyme, which is responsible for the hydroxylation of cross‐linking lysine residues in fibrillar collagen telopeptide domains. This modification enables collagen to form chemically stable (permanent) intermolecular cross‐links in the extracellular matrix. Normal bone collagen develops a unique mix of such stable and labile lysyl‐oxidase–mediated cross‐links, which contribute to bone strength, resistance to microdamage, and crack propagation, as well as the ordered deposition of mineral nanocrystals within the fibrillar collagen matrix. Bone from patients with BS caused by biallelic FKBP10 mutations has been shown to have abnormal collagen cross‐linking; however, to date, no direct studies of human bone from BS caused by PLOD2 mutations have been reported. Here the results from a study of a 4‐year‐old boy with BS caused by compound heterozygous mutations in PLOD2 are discussed. Diminished hydroxylation of type I collagen telopeptide lysines but normal hydroxylation at triple‐helical sites was found. Consequently, stable trivalent cross‐links were essentially absent. Instead, allysine aldol dimeric cross‐links dominated as in normal skin collagen. Furthermore, in contrast to the patient's bone collagen, telopeptide lysines in cartilage type II collagen cross‐linked peptides from the patient's urine were normally hydroxylated. These findings shed light on the complex mechanisms that control the unique posttranslational chemistry and cross‐linking of bone collagen, and how, when defective, they can cause brittle bones and related connective tissue problems. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Collagen transport and related pathways in Osteogenesis Imperfecta

“…The detrimental consequences of lack of LOX activity on collagen fibrillogenesis are seen after incubation of osteoblasts with the enzymatic inhibitor, β-aminopropionitrile (BAPN), as a result of which crosslinks and osteoblast differentiation are dysregulated (Turecek et al 2008 ). This is also in agreement with the defective crosslinking seen in patients with OI/Bruck syndrome patients with PLOD2 and FKBP10 mutations (Gistelinck et al 2020 ). This also highlights the need for impeccable coordination with COPI trafficking which delivers the FKBP65 back to the ER to make it available for procollagen hydroxylation.…”

Lysyl hydroxylase 2-induced collagen cross-link switching promotes metastasis in head and neck squamous cell carcinomas

“…Depending on the state of Lys hydroxylation in collagen telopeptides, 2 major cross-linking pathways are evolved: Lys ald - and Hyl ald -derived cross-links [63] , with the latter displaying enhanced stability over the former. Since LH2 is responsible for Lys hydroxylation in telopeptides, its activity is key to determining the stability, that is, “quality”, of collagen cross-linking [ 8 , 20 , 61 ]. While LH2 hyperactivity has been implicated in fibrosis for decades [ 59 , 60 ], mounting evidence suggests that LH2 upregulation can also drive proinvasive and prometastatic tumor behaviors across many different cancers.…”

“…However, the stability of collagen fibrils also depends on the quality/type of cross-links formed, not necessarily the quantity of cross-links alone. Collagens containing LH2-mediated stable cross-links are more resistant to degradation than those not modified by LH2 [ 8 , 20 , 61 ]. Moreover, such a stiffened and highly cross-linked tumor ECM may diminish accessibility of immune cells to the cancer cells within the TME.…”

“…These aldehydes then undergo a series of condensation reactions involving the juxtaposed Lys, Hyl and histidine (His) residues on the neighboring collagen molecules. The critical feature that determines the stability of cross-links is the state of Lys hydroxylation in telopeptides; Hyl ald -derived cross-links are more stable in comparison to Lys ald -derived cross-links [ 8 , 20 , 61 ]. The Lys hydroxylation reactions are catalyzed by lysyl hydroxylases 1-3 (LH1-3).…”

Lysyl hydroxylase 2 mediated collagen post-translational modifications and functional outcomes

“…Using a LH2 mutant zebra sh model, Gistelinck et al reported that Lys in the α1 C-telo of bone type I collagen (16 C ) was not hydroxylated in the mutant 24 , though neither Lys hydroxylation of the α1 and α2 N-telo domains nor the Hyl ald -or Lys ald -derived cross-links was analyzed in this study. More recently, Gistelinck et al reported detailed type I collagen phenotypes in bone obtained from a patient with Bruck syndrome 25 .…”