Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation

Abstract

According to current dogma, chondrocytes and osteoblasts are considered independent lineages derived from a common osteochondroprogenitor. In endochondral bone formation, chondrocytes undergo a series of differentiation steps to form the growth plate, and it generally is accepted that death is the ultimate fate of terminally differentiated hypertrophic chondrocytes (HCs). Osteoblasts, accompanying vascular invasion, lay down endochondral bone to replace cartilage. However, whether an HC can become an osteoblast and contribute to the full osteogenic lineage has been the subject of a century-long debate. Here we use a cell-specific tamoxifen-inducible genetic recombination approach to track the fate of murine HCs and show that they can survive the cartilageto-bone transition and become osteogenic cells in fetal and postnatal endochondral bones and persist into adulthood. This discovery of a chondrocyte-to-osteoblast lineage continuum revises concepts of the ontogeny of osteoblasts, with implications for the control of bone homeostasis and the interpretation of the underlying pathological bases of bone disorders.osteoblast ontogeny | chondrocyte lineage | bone repair I n vertebrates, the endochondral bones of the axial and appendicular skeleton (1) develop from mesenchymal progenitors that form condensations in the approximate shape of the future skeletal elements. These progenitors differentiate into chondrocytes, which proliferate, mature, and undergo hypertrophy, forming an avascular cartilaginous template surrounded by a perichondrium. The first osteoblasts differentiate from mesenchymal precursors in the perichondrium and produce a bone collar, which will become the future cortical bone (1). Blood vessels then invade through the bone collar into the hypertrophic cartilage, bringing in osteoblast progenitors from the perichondrium (2), which lay down bone matrix to form the primary ossification center (POC); the cartilage matrix is degraded; and the proximal and distal growth plates, comprising layers of differentiating chondrocytes and spongy/trabecular bone (the primary spongiosa), form (2). Thereafter, linear bone growth continues by endochondral ossification mediated by the growth plate, whereas osteoblasts in the perichondrium form cortical bone on the outer circumference.Chondrocytes and osteoblasts are regarded as separate lineages in development, being derived from common mesenchymal progenitors that express the transcription factors sex determining region Y (SRY)-box 9 (Sox9) and runt related transcription factor 2 (Runx2) (1). Lineage determination toward the chondrocyte or osteoblast fate is controlled by the relative expression of Sox9 and Runx2 (3-5) (Fig. 1A). Sox9 controls chondrocyte proliferation and their progression into hypertrophy (6). Collagen X is the most specific marker of hypertrophic chondrocytes (HCs), the Col10a1 gene being expressed only in prehypertrophic and hypertrophic chondrocytes in the growth plate (7). By contrast, Runx2 is essential for specifying the osteoblast lineage an...

Fibroblast growth factor signaling in skeletal development and disease

“…Chondrocyte hypertrophy leads to an expansive force that is required for bone elongation (Hunziker et al 1987;Hunziker and Schenk 1989;Noonan et al 1998). Hypertrophic chondrocytes can also begin to mineralize their extracellular matrix and have the capacity to differentiate into osteoblasts within the primary spongiosa (Yang et al 2014;Zhou et al 2014).…”

Fate of growth plate hypertrophic chondrocytes: Death or lineage extension?

“…In this study Cre recombinase was "knocked-in" to the Col10a1 gene (Yang et al 2014a). HCs specifically expressed Cre, which activated a reporter so that both HCs and their descendants were labelled and continued to express the reporter gene even when the Col10a1 promoter became inactive.…”

Artificial cartilage bio-matrix formed of hyaluronic acid and Mg2+-polyphosphate

“…However, evidence has been presented that terminally differentiated hypertrophic chondrocytes (Pacifici et al, 1990) can traverse to osteogenic cells both in foetal and postnatal endochondral bone (Yang et al, 2014). Osteoarthritis is characterised by a 20-fold increase in subchondral bone turnover and in an increased secretion of alkaline phosphatase (ALP) (Bailey et al, 2004), osteocalcin, osteopontin, IL-6 and IL-8 from subchondral bone explants in osteoarthritis patients (Mathy-Hartert et al, 2008 et al, 2001).…”