MMP14 cleaves PTH1R in the chondrocyte-derived osteoblast lineage, curbing signaling intensity for proper bone anabolism

Abstract

Bone homeostasis is regulated by hormones such as parathyroid hormone (PTH). While PTH can stimulate osteo-progenitor expansion and bone synthesis, how the PTH-signaling intensity in progenitors is controlled is unclear. Endochondral bone osteoblasts arise from perichondrium-derived osteoprogenitors and hypertrophic chondrocytes (HC). We found, via single-cell transcriptomics, HC descendent cells activate membrane-type 1 metalloproteinase 14 (MMP14) and the PTH pathway as they transition to osteoblasts in neonatal and adult mice. Unlike Mmp14 global knockouts, postnatal day 10 (p10) HC lineage-specific Mmp14 null mutants (Mmp14ΔHC) produce more bone. Mechanistically, MMP14 cleaves the extracellular domain of PTH1R, dampening PTH signaling, and consistent with the implied regulatory role, in Mmp14ΔHC mutants, PTH signaling is enhanced. We found HC-derived osteoblasts contribute ~50% of osteogenesis promoted by treatment with PTH 1-34 and this response was amplified in Mmp14ΔHC. MMP14 control of PTH signaling likely applies also to both HC- and non-HC-derived osteoblasts because their transcriptomes are highly similar. Our study identifies a novel paradigm of MMP14 activity-mediated modulation of PTH signaling in the osteoblast lineage, contributing new insights into bone metabolism with therapeutic significance for bone-wasting diseases.

The Origin and Fate of Chondrocytes: Cell Plasticity in Physiological Setting

“…This possibility becomes even more fascinating if we assume that the multipotent progenitors generated are long-lived skeletal stem cells (SSCs). This assumption is supported indirectly by the following observations: (i) the multipotency discussed above, (ii) the observation that descendants of Col10-positive chondrocytes labeled on postnatal day 9 in mice can be found in the bone marrow 16 months later [ 26 , 32 ••], and (iii) the fact that descendants of hypertrophic chondrocytes begin to express LepR [ 31 ••], and LepR + cells are currently considered to be SSPCs containing mostly SSCs [ 39 , 40 ] (Fig. 2 ).…”

“…Today, ample evidence obtained from the clonal lineage tracing [ 16 , 25 ], single-cell RNA sequencing (scRNAseq) [ 31 ••] and functional perturbations [ 32 ••] leaves no doubt that at least some hypertrophic chondrocytes undergo lineage extension to generate osteoblasts. In fact, certain estimates indicate that as much as 83% of the intramedullary osteoblasts originate from chondrocytes [ 31 ••], although multiple other reports propose that only approximately one-third to one-half of trabecular osteoblasts come from chondrocytes.…”

“…In fact, certain estimates indicate that as much as 83% of the intramedullary osteoblasts originate from chondrocytes [ 31 ••], although multiple other reports propose that only approximately one-third to one-half of trabecular osteoblasts come from chondrocytes. The variation in these estimates reflects differences in the efficiencies of the Cre lines employed, the methods by which the osteoblasts are co-labeled, and the time-point in development when the analysis is performed [ 24 – 26 , 31 ••, 32 ••]. Nonetheless, the clearly significant contribution of chondrocytes to the formation of osteoblasts provides an entirely new perspective on bone formation during endochondral ossification, as well as in connection with skeletal disease.…”

“…Yet, another factor recently discovered to be involved is parathyroid hormone (PTH), which promotes transdifferentiation of hypertrophic chondrocytes, while cleavage of its receptor (PTH1R) by MMP14 regulates the supply of chondrocyte-derived osteoblasts [ 32 ••]. scRNA-sequencing of Col10a1-Cre:tdTomato mice reveals that these osteoblasts are transcriptionally similar to and respond to PTH in the same manner as other osteoblasts, even as mice age [ 31 ••, 32 ••]. These latter observations indicate that osteoblasts that arise from two separate sources are morphologically, transcriptionally, and functionally similar.…”

PTH and the Regulation of Mesenchymal Cells within the Bone Marrow Niche

“…MMP14 can cleave PTH1R, particularly at amino acid 61, inhibiting its signaling activity. This cleavage by MMP14 promotes the degradation of PTH1R, serving as a novel mechanism for modulating the stability and signaling efficacy of this G protein-coupled receptor (GPCR), thus attenuating PTH signaling [ 236 ]. Additionally, cPTH treatment may also elevate the expression of CCL2, a chemokine that works alongside RANKL to facilitate the recruitment of monocytes, which then fuse to form mature, bone-resorbing osteoclasts [ 219 ].…”