Discoidin domain receptors; an ancient family of collagen receptors has major roles in bone development, regeneration and metabolism

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TL;DR

This review summarizes the roles of discoidin domain receptors (DDRs), particularly DDR2, in bone development, regeneration, and metabolism. DDR2 is expressed in skeletal progenitor cells and chondrocytes, where it regulates cell proliferation, differentiation, and collagen matrix organization, and its deficiency leads to severe skeletal defects and impaired bone regeneration. The findings highlight DDRs as potential therapeutic targets for conditions like osteoporosis, osteoarthritis, and heterotopic ossification.

Full summary

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**Background:** Collagens are the most abundant extracellular matrix (ECM) proteins, providing structural support to bones and teeth and conveying mechanical signals via specific collagen receptors. While integrins were long considered the primary collagen receptors in bone, the discoidin domain receptors (DDRs) are a more ancient family of receptor tyrosine kinases (RTKs) that bind triple-helical collagens. DDRs are present in most metazoans and may have primordial functions in collagen signaling. This review focuses on the roles of DDR1 and DDR2 in mineralized tissues, including bone, cartilage, and teeth, and their involvement in development, regeneration, and disease.

**Methods:** The review synthesizes findings from human genetic studies, global and conditional knockout mouse models, cell culture experiments, and lineage tracing analyses. Key techniques include immunohistochemistry, in situ hybridization, LacZ knock-in reporters, tamoxifen-inducible Cre recombination, and second harmonic generation microscopy. The authors also discuss transcriptional regulation, downstream signaling pathways (e.g., ERK/MAPK, p38, PI3K/AKT), and interactions with integrins.

**Key Results:** - **Human mutations:** Loss-of-function mutations in DDR2 cause spondylo-meta-epiphyseal dysplasia (SMED, SL-AC), characterized by dwarfism, short limbs, reduced bone mass, craniofacial abnormalities, and tooth defects. Gain-of-function mutations lead to Warburg-Cinotti Syndrome, with fibrosis, corneal vascularization, and osteolysis. - **Mouse models:** Global Ddr2 knockout mice (Ddr2^slie/slie) exhibit dwarfism, reduced trabecular bone volume (BV/TV reduced by ~50% in males), increased marrow fat, and craniofacial defects (shortened anterior-posterior skull, open fontanelles). Conditional knockout in Gli1+ skeletal progenitor cells recapitulates these phenotypes, while inactivation in mature osteoblasts (Bglap-Cre) has minimal effects. Ddr2 inactivation in chondrocytes (Col2a1-Cre) disrupts columnar organization, reduces proliferation, and impairs endochondral ossification. - **Bone regeneration:** Ddr2-deficient mice fail to heal calvarial defects (0.5 mm burr hole) even after 12 weeks, and tibial fractures show incomplete union. - **Signaling:** DDR2 activates ERK/MAPK and p38 pathways, leading to RUNX2 phosphorylation at Ser301/319, which promotes osteoblast differentiation. In Ddr2-deficient cells, reduced ERK activity decreases RUNX2 phosphorylation and increases PPARγ activity, shifting differentiation toward adipogenesis. - **Matrix organization:** DDR2 maintains collagen fibril orientation and ECM stiffness. In Ddr2 mutants, type II collagen distribution becomes pericellular, and fibril anisotropy is lost, disrupting chondrocyte polarity and proliferation. - **Disease involvement:** DDR1 promotes vascular calcification via PI3K/AKT and MAPK signaling. DDR2 is required for osteoarthritis induction in hyaline cartilage after injury and for heterotopic ossification after trauma. - **Metabolic effects:** Global Ddr2 deficiency elevates blood glucose, reduces body fat, and increases serum adiponectin. Adipocyte-specific Ddr2 knockout protects against high-fat diet-induced weight gain and increases bone mass via cAMP-mediated lipolysis.

**Clinical Implications:** DDRs are critical for skeletal development, regeneration, and metabolism. DDR2 deficiency severely impairs bone formation and repair, while DDR1 contributes to vascular calcification. These findings suggest that DDR inhibitors (e.g., for DDR2 in osteoarthritis or heterotopic ossification) or activators (e.g., for bone regeneration) could have therapeutic potential. The review also highlights the interplay between DDRs and integrins in mechanotransduction and matrix organization, offering new targets for treating skeletal disorders.