Osteocyte Death and Bone Overgrowth in Mice Lacking Fibroblast Growth Factor Receptors 1 and 2 in Mature Osteoblasts and Osteocytes

Abstract

Fibroblast growth factor (FGF) signaling pathways have well‐established roles in skeletal development, with essential functions in both chondrogenesis and osteogenesis. In mice, previous conditional knockout studies suggested distinct roles for FGF receptor 1 (FGFR1) signaling at different stages of osteogenesis and a role for FGFR2 in osteoblast maturation. However, the potential for redundancy among FGFRs and the mechanisms and consequences of stage‐specific osteoblast lineage regulation were not addressed. Here, we conditionally inactivate Fgfr1 and Fgfr2 in mature osteoblasts with an Osteocalcin (OC)‐Cre or Dentin matrix protein 1 (Dmp1)‐CreER driver. We find that young mice lacking both receptors or only FGFR1 are phenotypically normal. However, between 6 and 12 weeks of age, OC‐Cre Fgfr1/Fgfr2 double‐ and Fgfr1 single‐conditional knockout mice develop a high bone mass phenotype with increased periosteal apposition, increased and disorganized endocortical bone with increased porosity, and biomechanical properties that reflect increased bone mass but impaired material properties. Histopathological and gene expression analyses show that this phenotype is preceded by a striking loss of osteocytes and accompanied by activation of the Wnt/β‐catenin signaling pathway. These data identify a role for FGFR1 signaling in mature osteoblasts/osteocytes that is directly or indirectly required for osteocyte survival and regulation of bone mass during postnatal bone growth. © 2019 American Society for Bone and Mineral Research.

FGF/FGFR signaling in health and disease

“…185 FGFR1 signaling in mature osteoblasts/osteocytes is required for the survival of osteocytes and bone mass maintaining in mice. 186 In addition, our group revealed that FGFR1 can positively regulate the differentiation and resorption activity of osteoclasts. 187 GOF mutation in FGFR2 (S252W) resulted in increased apoptosis of osteogenic cells, 188 disturbed osteoblastic proliferation and differentiation, and the presence of ectopic cartilage at the midline sagittal suture.…”

“… 185 FGFR1 signaling in mature osteoblasts/osteocytes is required for the survival of osteocytes and bone mass maintaining in mice. 186 In addition, our group revealed that FGFR1 can positively regulate the differentiation and resorption activity of osteoclasts. 187 …”

Erythropoietin signaling in osteoblasts is required for normal bone formation and for bone loss during erythropoietin‐stimulated erythropoiesis

“…Osteoblasts lining the trabecular bone were identified from the H & E stained femur sections, number of cells were expressed in terms of the bone surface. H & E stained sections were also used for enumerating alive, dying, and dead osteocytes in the cortical bones using a previously published method 14 . For osteoclast detection in femurs, Tartrate‐resistant acid phosphatase (TRAP) staining was performed using TRAP/ALP Stain Kit according to manufacturer's instructions (#294‐67001, Wako Chemicals, USA).…”

Fibroblast growth factors signaling in bone metastasis

“…Similar findings were observed after conditional inactivation of Fgfr1 and Fgfr2 in osteocytes. These data suggest that FGFR1 and/or FGFR2 expression in mature osteoblasts/osteocytes is required for osteocyte survival and regulation of bone mass during postnatal bone growth (McKenzie et al 2019). A previous report indicated that conditional knockout of Fgfr1 in osteocytes in mice results in decreased osteocyte-specific gene expression but no overt skeletal phenotype (Xiao et al 2014).…”