Enhanced BMP signaling via ALK2 in osteoclasts decreases bone density in mice.

Overview

Bone remodeling is a critical biological process required for bone homeostasis. Osteoclasts are essential skeletal cells for bone resorption, and pathological activation of osteoclastogenesis results in bone volume loss. A prior study suggests that bone morphogenetic protein (BMP) signaling via one of the BMP type I receptors, ALK2, positively regulates osteoclastogenesis in vitro. However, the mechanisms of how the activation of BMP signaling affects osteoclastogenesis in vivo remain elusive. To address this question, we utilized two osteoclast-specific Cre mice, Lysosome 2 (LysM)-Cre mice and Cathepsin K (Ctsk)-Cre, that enabled us to activate BMP signaling in osteoclast progenitors and/or mature osteoclasts, respectively. We then investigated the effect of osteoclast lineage-specific upregulation of BMP signaling via ALK2 by crossing constitutively active ALK2 (ca-Alk2) mice (hereafter ca-Alk2:LysM-Cre and ca-Alk2:Ctsk-Cre). Compared with controls, ca-Alk2:LysM-Cre and ca-Alk2:Ctsk-Cre mice displayed osteopenic phenotypes. While the number of RUNX2-positive osteoblasts was unchanged, we found the number of tartrate-resistant acid phosphatase (TRAP)- and CTSK-positive cells in the femur was significantly increased in both ca-Alk2:Ctsk-Cre and ca-Alk2:LysM-Cre mice. Our study suggests that enhanced BMP signaling in osteoclasts promotes osteoclastogenesis in an osteoclast-autonomous manner, leading to reduced bone volume in mice.