DMP1-Cre expressing cells mediate the gain in bone mass and strength, but not the increase in bone remodeling, induced by ligands of the parathyroid hormone receptor.
DMP1-Cre expressing cells are essential for bone mass gain induced by abaloparatide, but not for increased bone remodeling.
Where it sits
this study against the rest of the abaloparatide (tymlos) corpusSummary and findings
The study investigated the role of DMP1-Cre expressing cells in mediating the effects of abaloparatide and parathyroid hormone on bone mass and strength in diabetic and control mice. Abaloparatide and parathyroid hormone increased bone mass and strength in mice with intact PTH1R in osteocytes but not in those lacking it. Bone remodeling was increased regardless of PTH1R presence in osteocytes.
Abstract
Signaling downstream of the receptor of parathyroid hormone (PTH1R) exerts two major skeletal effects: increases bone remodeling and, when stimulated intermittently, induces bone anabolism. Osteocytes express the PTH1R and are critical for the action of teriparatide/parathyroid hormone 1-34 (PTH). However, it is unknown whether they also mediate the effects of abaloparatide (a 34 amino acid synthetic analog of human parathyroid hormone-related protein, ABL), and whether actions on osteocytes are required for the increase in remodeling and/or the bone gain induced by PTH/ABL in diabetes. We addressed these questions by treating with PTH or ABL control or diabetic (DM) mice lacking the PTH1R in DMP1-Cre expressing cells that targets all osteocytes (cKO). Both PTH and ABL increased bone mass and improved or corrected cortical and trabecular bone microarchitecture only in fl/fl littermates but not in cKO, control or DM mice. Further, PTH/ABL increased bone strength and microindentation resistance only in control or DM fl/fl mice. In contrast, PTH/ABL increased serum P1NP and bone formation on cancellous, periosteal and endocortical surfaces, in control or DM mice of both genotypes. Moreover, serum CTX and osteoclast surface were increased by PTH/ABL in fl/fl and cKO, control or DM mice. Thus, actions on DMP1-Cre expressing cells are required for bone gain, microarchitecture restoration, strength and resistance to fracture, exerted by PTH and ABL under physiological and DM conditions, but not for the increase in bone remodeling. These findings demonstrate the dissociation of bone gain from bone remodeling and reveal that actions on DMP1-Cre expressing cells drive the gain in bone mass and strength induced by PTH and ABL.
Background
The study addresses the role of DMP1-Cre expressing cells in mediating the skeletal effects of parathyroid hormone receptor ligands, specifically abaloparatide. Previous research has established that PTH1R signaling increases bone remodeling and anabolism, but the specific contribution of osteocytes, particularly in the context of abaloparatide, remains unclear. Understanding these mechanisms is crucial for developing targeted therapies for bone disorders, especially in diabetic conditions.
Methods
The study utilized a mouse model with conditional knockout (cKO) of the PTH1R in DMP1-Cre expressing cells, targeting osteocytes. Both control and diabetic mice were treated with either parathyroid hormone or abaloparatide. The primary outcomes measured included bone mass, microarchitecture, strength, and biochemical markers of bone turnover. The effects were compared between mice with intact PTH1R (fl/fl) and those with the receptor knocked out (cKO).
Results
The primary finding was that both parathyroid hormone and abaloparatide increased bone mass and improved bone microarchitecture only in fl/fl mice, not in cKO mice. Bone strength and resistance to fracture were similarly enhanced only in fl/fl mice. However, increases in serum P1NP, bone formation, serum CTX, and osteoclast surface were observed in both genotypes, indicating that bone remodeling was independent of PTH1R presence in osteocytes.
Interpretation
The study reveals a dissociation between bone mass gain and remodeling, suggesting that DMP1-Cre expressing cells are crucial for the former but not the latter. This finding contrasts with previous assumptions that bone remodeling and mass gain are interdependent. The results imply that targeting specific cell types could enhance therapeutic strategies for bone disorders, though the clinical relevance remains uncertain due to the animal model used.
Key findings
- PTH/ABL increased bone mass only in fl/fl littermates, not in cKO mice.
- Bone strength and microindentation resistance increased only in fl/fl mice.
- Serum P1NP and bone formation increased in both genotypes.
- Serum CTX and osteoclast surface increased in all genotypes.
- DMP1-Cre cells required for bone gain but not for remodeling.
Limitations
- mouse model, not human data
- focus on DMP1-Cre expressing cells
- conditional knockout limits generalizability
- unknown long-term effects
- potential differences in diabetic vs non-diabetic responses